Condensed heterocyclic ketone derivatives and their use

ABSTRACT

A compound of the formula: ##STR1## wherein R 1  is H or an optionally substituted hydrocarbon or acyl group; ring A is an optionally further substituted benzene ring; n is an integer of 1 to 10; R 2 , R 3  and R 4  are H or an optionally substituted hydrocarbon group; R 3  and R 4  may form an optionally substituted heterocyclic group, taken together with the adjacent nitrogen atom; k is an integer of 0 to 3; and m is an integer of 1 to 8; provided that when k=0 and m=2, n is an integer of not less than 2 or a pharmaceutically acceptable salt thereof, exhibiting excellent cholinesterase inhibitory activity and monoamine reuptake inhibitory activity, thus being useful as therapeutic/prophylactic medicaments of senile dementia.

This invention relates to novel condensed heterocyclic ketonederivatives and salts thereof. These compounds are useful as medicines,more specifically, cholinesterase inhibitors, especially as therapeuticor/and prophylactic agents for senile dementia, Alzheimer's disease andso on.

With an increasing number of elderly people, there have been proposedvarious compounds having therapeutic and/or prophylactic actions onsenile dementia. Among them, in physostigmine, a naturally-occurringcholinesterase inhibitor, there has been found therapeutic or/andprophylactic actions on senile dementia (International Journal ofClinical Pharmacology, Therapy and Toxicology, Vol. 29, No. 1, p.23-37(1991) etc.). Physostigmine is, however, possessed of suchdrawbacks as relatively short duration of the action and high toxicity.

On the other hand, various heterocyclic compounds have been proposed assynthetic medicines (for example, in EP-A-0,378,207, U.S. Pat. No.4,849,431 and U.S. Pat. No. 4,895,841, cholinesterase inhibitors havingN-containing heterocyclic ring being described, and, in JPAS52(1977)-72829 and JPA S55(1980)-9070, antidepressant or antianxietydrugs having chemical structures analogous to the above-mentionedcholinesterase inhibitor being described).

More specifically, in EP-A-0,378,207, there are disclosed cyclic aminecompounds represented by the formula: ##STR2## wherein B stands for anoptionally substituted saturated or unsaturated 5- to 7-memberedazaheterocyclic group; A stands for a bond or an alkylene group oralkenylene group optionally substituted with a hydrocarbon residue, oxogroup or hydroxyl group; ----- means a single bond or double bond(provided that, when A stands for a bond, ----- means single bond); R₂and R₃ independently stand for H or an optionally substitutedhydrocarbon residue (provided that they are not H at the same time) ormay form a cyclic amino group taken together with the adjacent nitrogenatom; n denotes 0, 1 or 2; p denotes 1 or 2, or salts thereof,practically the following compound, among others. ##STR3##

In U.S. Pat. No. 4,849,431, there are disclosed piperidine derivativesrepresented by the formula:

    R.sup.1 --X--A--R.sup.2

wherein R¹ stands for a monovalent group derived from a member selectedfrom optionally substituted benzene, pyridine, pyrazine, indole,anthraquinone, quinoline, optionally substituted phthalimide,homophthalimide, pyridine carboxylimide, pyridine-N-oxide, pyrazinecarboxylimide, naphthalenedicarboxylimide, optionally substitutedquinazolinedione, 1,8-naphthalimide,bicyclo[2,2,21oct-5-ene-2,3-dicarboxylimide and pyromellylimide;

X stands for a group shown by the formula: --(CH₂)_(m) -- (wherein mdenotes a whole number of 0 to 7), a group shown by the formula:--O(CH₂)_(n) --, a group shown by the formula: --S(CH₂)_(n), a groupshown by the formula: --NH(CH₂)_(n) --, a group shown by the formula:--SO₂ NH(CH₂)_(n) --, a group shown by the formula: --NH--CO--(CH₂)_(n)--, a group shown by the formula: --NH(CH₂)_(n) --CO--, a group shown bythe formula: --CO--NR³ --(CH₂)_(n) -- (in the definition of X, n in theabove formulae denotes a whole number of 1 to 7, and R³ stands for alower alkyl or benzyl group), a group shown by the formula: --O--CH₂ CH₂CH(CH₃)--, a group shown by the formula: --O--CH₂ CH₂ CH═, or a groupshown by the formula: --O--CH₂ CH(OH)CH₂ --;

Ring A stands for a group shown by the formula: ##STR4## a group shownby the formula: ##STR5## a group shown by the formula: ##STR6## a groupshown by the formula: ##STR7## R² stands for H, a lower alkyl group,optionally substituted benzyl group, optionally substituted benzoylgroup, pyridyl group, 2-hydroxyethyl group, pyridylmethyl group, or agroup shown by the formula: ##STR8## (wherein Z stands for a halogenatom), or pharmaceutically acceptable salts thereof, practically thefollowing compound. ##STR9##

In U.S. Pat. No. 4,895,841, there are disclosed cyclic amine derivativesrepresented by the general formula: ##STR10## wherein J stands for (a)optionally substituted groups shown as follows; (1) phenyl group, (2)pyridyl group, (3) pyrazyl group, (4) quinolyl group, (5) cyclohexylgroup, (6) quinoxalyl group or (7) furyl group,

(b) a mono- or di-valent group selected from the following groupsoptionally substituted with a phenyl group; (1) indanyl, (2) indanonyl,(3) indenyl, (4) indenonyl, (5) indanedionyl, (6) tetralonyl, (7)benzsperonyl, (8) indanolyl, (9) a group shown by the formula: ##STR11##(c) a monovalent group derived from a cyclic amido compound, (d) a loweralkyl group, or

(e) a group shown by the formula: R¹ --CH═CH-- (wherein R¹ stands for Hor a lower alkoxycarbonyl group); B stands for a group shown by theformula: --(C(R²)H)_(n) --, a group shown by the formula:--CO--(C(R²)H)_(n) --, a group shown by the formula: --NR²--(C(R²)H)_(n) -- (wherein R² stands for H, a lower alkyl group, acylgroup, a lower alkylsulfonyl group, optionally substituted phenyl groupor benzyl group), a group shown by the formula: --CO--NR⁴ --(C(R²)H)_(n)-- (wherein R⁴ stands for H, a lower alkyl group or phenyl group), agroup shown by the formula: --CH═CH--(C(R²)H)_(n) --, a group shown bythe formula: --O--COO--(C(R²)H)_(n) --, a group shown by the formula:--O--CO--NH--(C(R²)H)_(n) --, a group shown by the formula:--NH--CO--(C(R²)H)_(n) --, a group shown by the formula: --CH₂--CO--NH-- (C(R²)H)_(n) --, a group shown by the formula:--CO--NH--(C(R²)H)_(n) --, a group shown by the formula:--C(OH)H--(C(R²)H_(n) -- (in the above formulae, n denotes 0 or a wholenumber of 1 to 10, R² stands for H or a methyl group in the form of thealkylene group shown by the formula: --(C(R²)H)_(n) -- which isunsubstituted or having one or more than one methyl group), a groupshown by the formula: ═(CH--CH═CH)_(b) -- (wherein b denotes a wholenumber of 1 to 3), a group shown by the formula: ═CH--(CH₂)_(c) --(wherein c denotes a whole number of 1 to 9), a group shown by theformula: ═(CH--CH)_(d) ═ (wherein d denotes 0 or a whole number of 1 to5), a group shown by the formula: --CO--CH--CH--CH₂ --, a group shown bythe formula: --C(CH₃)H--CO--NH--CH₂ --, a group shown by the formula:--CH═CH--CO--NH--(CH₂)₂ --, the group shown by the formula: --NH--, thegroup shown by the formula: --O--, the group shown by the formula:--S--,, dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group,

T stands for N or C,

Q stands for N, C or a group shown by the formula: >N→O,

K stands for H, an optionally substituted phenyl group, an arylalkylgroup optionally substituted with a phenyl group, a cinnamyl groupoptionally substituted with a phenyl group, a lower alkyl group,pyridylmethyl group, cycloalkylalkyl group, adamantanemethyl group,furylmethyl group, cycloalkyl group, a lower alkoxycarbonyl group oracyl group,

q denotes a whole number of 1 to 3, and ----- denotes a single bond or adouble bond or their pharmaceutically acceptable salts, a practicalembodiment being the following compound. ##STR12##

In U.S. Pat. No. 4,064,255, there are disclosed pharmaceuticalcompositions containing a compound represented by the general formula:##STR13## wherein R stands for H, a C₁₋₄ alkyl group or an aralkyl groupwhose alkyl moiety has one or two carbon atoms; X stands for H or ahalogen atom, alkyl, alkoxy or alkylthio group, each optionally havingone to four carbon atoms, trifluoromethyl, nitro, hydroxyl orunsubstituted amino group or amino group substituted with one or twoalkyl groups or acyl or alkylsulfonyl group; A stands for the group--CO-- or the group --CH₂ --; and n denotes 0, 1 or 2, or apharmaceutically acceptable salt thereof, which are useful in treatmentof pathological conditions caused by disturbances in serotonin systems,and, in U.S. Pat. No. 4,208,417, there are disclosed indole derivativesrepresented by the general formula: ##STR14## wherein R stands for H, aC₁₋₄ alkyl group or an aralkyl group whose alkyl moiety has one or twocarbon atoms; X stands for H or a halogen atom, alkyl group, alkoxygroup or an alkylthio group whose alkyl moiety has one to four carbonatoms; A stands for --CO-- or --CH₂ --; and n denotes 1 or 2, which aremedicinally active compounds having affinity for the ³ H-diazepambinding site.

Further, in WO91/03243, there are disclosed compounds represented by thegeneral formula: ##STR15## wherein m denotes 0 to 3; n denotes 0 to 3; mand n are not 0 simultaneously; p denotes 0 to 3; X stands for O S, SO,SO₂, NR⁶, CR⁷ R⁸, CO or CHOH; R¹, R³ and R⁷ each stand for H, C₁₋₅alkyl, halogen, NR¹⁰ R¹¹, OH, COOH, C₂₋₆ carboalkoxy, CN, Ar, C₁₋₅alkoxy or C₁₋₅ alkylthio; R², R⁴ and R⁸ each stand for H, C₁₋₅ alkyl,C₂₋₆ carboalkoxy, CN, C₁₋₅ alkoxy or Ar¹ ; when X is O, S, SO, SO₂ orNR⁶, R¹, R², R³ and R⁴ are not C₁₋₅ alkoxy, C₁₋₅ alkylthio, NR¹⁰ R¹¹ orOH; R⁵ stands for H, alkyl, halogen, OH or alkenyl; R⁶ stands for H,C₁₋₅ alkyl or Ar¹ ; Ar and Ar¹ respectively stand for naphthyl, pyridyl,pyrimidyl, indolyl, quinolinyl or phenyl, these groups being optionallysubstituted with C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl having 1 to 7halogen atoms, SH, S(O)_(t) --C₁₋₃ alkyl ( t denotes 1, 2 or 3 ), C₂₋₆dialkylamino, halogen, C₁₋₃ alkylamino, NH₂, CN, NO₂, SO₃ H, tetrazole,COOH, C₂₋₆ carboalcoxy, CONH₂, SO₂ NO₂, COR⁹, CONR¹² R¹³, SO₂ NR¹² R¹³,Ar², OAr² or SAr² ; Ar² stands for a naphthyl group or phenyl group,these groups being optionally substituted with C₁₋₃ alkyl, C₁₋₃haloalkyl having one to seven halogen atoms, C₁₋₃ alkoxy, halogen orC₁₋₃ alkylthio; R⁹, R¹⁰, R¹¹, R¹² and R¹³ respectively stand for H, C₁₋₅alkyl or phenyl, R¹⁰ and R¹¹ may, taken together, form C₃₋₆ alkylenechain, R¹² and R¹³ may, taken together, form C₃₋₆ alkylene chain; a or bshows double bond or single bond, and both are not double bond, orpharmaceutically acceptable salts thereof, which are useful in thetreatment of physiological or drug-induced psychosis or dyskinesia.

On the other hand, a variety of O-containing or S-containing condensedketone derivatives have been produced, and their biological activity andpharmacological actions are disclosed. However, nothing was disclosed asto action as cholinesterase inhibitors and therapeutic and/orprophylactic agents of senile dementia.

More specifically, in Chem. Abstr., 107, 190332h (1987), there isdisclosed that the compound represented by the general formula:##STR16## (wherein R=Ac, COEt, COPr, COCHMe₂, CO(CH₂)₂ Cl, CO(CH₂)₃ Cl,COCH₂ NMe₂, CO(CH₂)₂ NMe₂, CO(CH₂)₃ NMe₂, and salts of them orR═COCH═CHPh, X═CH₂ or O, n=1, 2 or 3) has an antiinflammatory action. InChem. Abstr., 89, 36594y (1978), there is disclosed that the compoundrepresented by the general formula: ##STR17## (wherein R¹ ═H, Me; n=2,3) has a convulsive action, an 1 arterial blood pressure lowering actionand a local anesthetic action.

In Chem. Abstr., 87, 152125d (1977), there is disclosed that thecompound represented by the general formula: ##STR18## wherein R¹ ═H,Me; R═H, Cl, Me; R³ ═H, F, Me, OMe, Cl; n=1, 2, 3; Z═O, OH, H (forCompound I) or R² ═H, Cl; R⁴ ═H, Me; NR⁵ ═NMe₂, morpholino, piperidino(for Compound 4 II) has an antidepressant action.

In EP-163,537, there is disclosed the compound represented by thegeneral formula: ##STR19## (wherein R═4-cycloalkylphenyl,3,4-methylenedioxyphenyl, 2,3-dihydro-5-benzofuranyl; R¹ ═alkyl,cycloalkyl, cyclopentylmethyl; R² ═optionally substituted pyrrolidino,piperidino, hexahydro-1H-azepin-1-yl, octahydro-1-azocinyl) has amuscle-relaxing action.

In Chem. Abstr., 91, 211631y (1979), there is disclosed that thecompound represented by the formula: ##STR20## (wherein R═H, Me) issynthesized as a derivative of cytisine, an alkaloid, having ananticholinergic action.

And, as N-containing condensed heterocyclic ketone derivatives, inHelvetica Chimica Acta, 51, 1616 (1968), the compounds represented bythe formula (A) and the formula (B): ##STR21## are disclosed asintermediates for synthesizing alkanolamine, an agent acting on thesympathetic nervous system, represented by the formula (C): ##STR22##

In these days when senile dementia is increasing, however, there isneeded development of excellent therapeutic and/or prophylactic agentshaving a stronger action and longer action and less toxicity than thecompounds already known to have therapeutic and/or prophylactic efficacyon senile dementia.

The present invention was accomplished by succeeding in creation ofnovel compounds having a condensed heterocyclic group of specificchemical structure and by finding that these novel compounds haveunexpectedly excellent cholinesterase inhibitory activity and monoaminereuptake inhibitory activity, thus being useful as therapeutic and/orprophylactic agents for senile dementia. More specifically, the presentinvention relates to;

(1) condensed heterocyclic ketone derivatives of the formula: ##STR23##wherein R¹ stands for H, an .optionally substituted hydrocarbon group oran optionally substituted acyl group; ring A stands for an optionallyfurther substituted benzene ring; n denotes a whole number of 1 to 10;R², R³, and R independently stand for H or an optionally substitutedhydrocarbon group; R³ and R⁴ may form an optionally substitutedheterocyclic group, taken together with the adjacent nitrogen atom; theR² 's may be different from one another in the repetition of n; kdenotes a whole number of 0 to 3; and m denotes a whole number of 1 to8; provided that when k=0 and m=2, n denotes a whole number of not lessthan 2, or salts thereof,

(2) a method of producing the compound [I]or a salt thereof, whichcomprises reacting a compound represented by the formula: ##STR24##wherein Y stands for a leaving group; R¹, ring A, R², n, k and m are ofthe same meanings as defined above, or a salt thereof with a compoundrepresented by the formula: ##STR25## wherein R³ and R⁴ are of the samemeanings as defined above, or a salt thereof,

(3) a method of producing a compound represented by the formula:##STR26## wherein R¹, R³, R⁴, ring A, k and m are of the same meaningsas defined above, R⁵ stands for H or an optionally substitutedhydrocarbon group, and R⁶ stands for H or an optionally substitutedhydrocarbon group, or a salt thereof, which comprises reacting acompound represented by the formula: ##STR27## wherein R¹, R⁵, ring A, kand m are of the same meanings as defined above, or a salt thereof and acompound represented by the formula:

    R.sup.6 --CHO                                              [V]

wherein R⁶ is of the same meaning as defined above with a compoundrepresented by the formula ##STR28## wherein R³ and R⁴ are Of the samemeanings as defined above, or a salt thereof,

(4) compounds represented by the formula: ##STR29## wherein Y, R¹, ringA, R², n, k and m are of the same meanings as defined above, or saltsthereof,

(5) a cholinesterase inhibitor, which contains a condensed heterocyclicketone derivative represented by the formula: ##STR30## wherein X¹stands for R¹ --N (wherein R¹ stands for H, an optionally substitutedhydrocarbon group or an optionally substituted acyl group), O or S; ringA stands for an optionally further substituted benzene ring; n denotes awhole number of 1 to 10; R², R³ and R⁴ independently stand for H or anoptionally substituted hydrocarbon group; R³ and R⁴ may form anoptionally substituted heterocyclic group, taken together with theadjacent nitrogen atom; R² 's may be different from one another in therepetition of n; k denotes a whole number of 0 to 3; and m denotes awhole number of 1 to 8, or a salt thereof, and

(6) a therapeutic and/or prophylactic agent for senile dementia whichcontains the compound [VII] or a salt thereof.

The compound [I] or salts thereof of this invention are novel compoundshaving structural characteristics in that the heterocyclic ringcontaining a hetero atom (O, S or N) condensed on the benzene ring is asaturated one and a substituent ##STR31## is bonded to the carbon atomon the benzene ring, and, based on these characteristics, thesecompounds show excellent therapeutic or/and prophylactic actions forsenile dementia.

In the foregoing formulae, R¹ stands for H, an optionally substitutedhydrocarbon group or an optionally substituted acyl group.

R² stands for H or an optionally substituted hydrocarbon group, and theR² 's may be different from one another in the repetition of n.

R³ and R⁴ stand for H or an optionally substituted hydrocarbon group,and, they may form, taken together with the adjacent nitrogen atom, anoptionally substituted heterocyclic group.

R⁵ and R⁶ stand for H or an optionally substituted hydrocarbon group.

Examples of "hydrocarbon group" of the "optionally substitutedhydrocarbon group" shown by the above-mentioned R¹, R², R³, R⁴, R⁵ andR⁶ include chain-like or cyclic or their combined type C₁₋₁₈ hydrocarbongroups. Examples of the chain-like hydrocarbon groups includestraight-chain or branched C₁₋₁₁ alkyl groups (e.g. methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl,etc.), straight-chain or branched C₂₋₄ alkenyl groups (e.g. vinyl,allyl, 2-butenyl, etc.) and straight-chain or branched C₂₋₄ alkynylgroups (e.g. propargyl, 2-butynyl, etc.). Examples of the cyclichydrocarbon groups include C₃₋₇ monocyclic cycloalkyl groups (e.g.cyclobutyl, cyclopentyl, cyclohexyl etc.), C8-14 bridge ring saturatedhydrocarbon groups (e.g. bicyclo[3.2.1]oct-2-yl, bicyclo[3.3.1]non-2-yl,adamantan-1-yl, etc.), C₆₋₁₄ aryl groups (e.g. phenyl group, naphthylgroup, etc.), among others.

Examples of hydrocarbon groups composed of chain-like and cyclic onesinclude C7-18 aralkyl (phenyl-C₁₋₁₂ alkyl or naphthyl-C₁₋₈ alkyl such asphenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl,phenylhexyl or α-naphthylmethyl; diphenyl-C₁₋₃ alkyl such asdiphenylmethyl or diphenylethyl), C₆₋₁₄ aryl-C₂₋₁₂ alkenyl (phenyl-C₂₋₁₂alkenyl such as styryl, cinnamyl, 4-phenyl-2-butenyl or4-phenyl-3-butenyl), C₆₋₁₄ aryl-C₂₋₁₂ alkynyl (phenyl-C₂₋₁₂ alkynyl suchas phenylethynyl, 3-phenyl-2-propynyl or 3-phenyl-1-propynyl), C₃₋₇cycloalkyl-C₁₋₆ alkyl (e.g. cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl,cycloheptylethyl, cyclopropylpropyl, cyclobutylpropyl,cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl,cyclopropylbutyl, cyclobutylbutyl, cyclopentylbutyl, cyclohexylbutyl,cycloheptylbutyl, cyclopropylpentyl, cyclobutylpentyl,cyclopentylpentyl, cyclohexylpentyl, cycloheptylpentyl,cyclopropylhexyl, cyclobutylhexyl, cyclopentylhexyl, cyclohexylhexyl,cycloheptylhexyl, etc.).

Preferable examples of the "hydrocarbon group" of the "optionallysubstituted hydrocarbon group" shown by R¹, R², R³, R⁴, R⁵ and R⁶include straight-chain or branched C₁₋₁₁ alkyl groups, especiallystraight-chain or branched C₁₋₇ alkyl groups (e.g. methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl,etc.) or C₇₋₁₈ aralkyl groups, especially C₇₋₁₀ aralkyl groups (e.g.phenyl-C₁₋₄ alkyl such as phenylmethyl, phenylethyl and phenylpropyl).

The hydrocarbon groups shown by R¹, R², R³, R⁴, R⁵ and R⁶ may optionallyhave substituents, and, as such substituents, use is properly made ofthose generally used as substituents of hydrocarbon groups. Morespecifically, as substituents which the above-mentioned C₁₋₁₁ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇ monocyclic cycloalkyl and C₈₋₁₄ bridgering saturated hydrocarbon groups may have, use is made of one to fiveof those selected from halogen atoms (e.g. fluorine, chlorine, bromine,iodine, etc.), nitro group, cyano group, hydroxyl group, C₁₋₄ alkoxygroups (e.g. methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.),C₁₋₄ alkylthio groups (e.g. methylthio, ethylthio, propylthio, etc.),amino group, mono- or di- C₁₋₄ alkylamino group (e.g. methylamino,ethylamino, propylamino, dimethylamino, diethylamino, etc.), 5- to7-membered cyclic amino groups (e.g. pyrrolidino, piperidino,morpholino, etc.), C₁₋₄ alkyl-carbonylamino groups (e.g. acetylamino,propionylamino, butyrylamino, etc.), C₁₋₄ alkylsulfonylamino groups(e.g. methylsulfonylamino, ethylsulfonylamino, etc.), C₁₋₄alkoxy-carbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, etc.), carboxyl group, C₁₋₆ alkyl-carbonyl groups (e.g.methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.), carbamoyl group,mono- or di-C₁₋₄ alkylcarbamoyl groups (e.g. methylcarbamoyl,ethylcarbamoyl, etc.), alkylsulfonyl groups (e.g. methylsulfonyl,ethylsulfonyl, propylsulfonyl, etc.), C₁₋₄ alkylenedioxy (e.g.methylenedioxy, etc.), 5- or 6- membered heterocyclic groups or itscondensed ring containing 1 to 3 hetero atoms selected from N,S and Oother than carbon atoms which may be substituted with a C₁₋₄ alkyl (e.g.pyridyl, pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl,naphthylidinyl, thiazolyl, benzothiazolyl, benzoxazolyl, furyl, furanyl,thiophenyl, etc.).

Examples of the substituents, which the C₆₋₁₄ aryl groups shown by R¹,R², R³, R⁴, R⁵ and R⁶ may have, include C₁₋₄ alkyl groups (e.g. methyl,ethyl, propyl, butyl, etc.), halogen atoms (e.g. fluorine, chlorine,bromine, iodine, etc.), nitro group, cyano group, hydroxyl group, C₁₋₄alkoxy groups (e.g. methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy,etc.), C₁₋₄ alkylthio groups (e.g. methylthio, ethylthio, propylthio,isopropylthio, butylthio, etc.), amino group, mono- or di-C₁₋₄alkylamino groups (e.g. methylamino, ethylamino, propylamino,dimethylamino, diethylamino, etc.), 5- to 7-membered cyclic amino groups(e.g. pyrrolidino, piperidino, morpholino, etc.), C₁₋₄alkyl-carbonylamino groups (e.g. acetylamino, propionylamino,butyrylamino, etc.), C₇₋₁₈ aralkyloxy (e.g. phenylmethoxy, phenylethoxy,etc.), aminocarbonyloxy group, mono- or di-C₁₋₄ alkylaminocarbonyloxygroups (e.g. methylaminocarbonyloxy, ethylaminocarbonyloxy,dimethylaminocarbonyloxY, diethylaminocarbonyloxy, etc.), C₁₋₄alkylsulfonylamino groups (e.g. methylsulfonylamino, ethylsulfonylamino,propylsulfonylamino, etc.), C₁₋₄ alkoxy-carbonyl groups (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl,etc.), carboxyl group, C₁₋₆ alkyl-carbonyl groups (e.g. methylcarbonyl,ethylcarbonyl, butylcarbonyl, etc.), C3-7 cycloalkyl-carbonyl (e.g.cyclohexylcarbonyl, etc.), carbamoyl group, mono- or di-C₁₋₄alkyl-carbamoyl groups (e.g. methylcarbamoyl, ethylcarbamoyl,propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl,etc.), alkylsulfonyl groups (e.g. methylsulfonyl, ethylsulfonyl,propylsulfonyl, etc.), cycloalkylsulfonyl (e.g. cyclopentylsulfonyl,cyclohexylsulfonyl, etc.), C₁₋₄ alkylenedioxy (e.g. methylenedioxy,etc.) as well as phenyl, naphthyl, mono- or di-phenyl-C₁₋₃ alkyl (e.g.benzyl, diphenylmethyl, etc.), phenoxy, benzoyl, phenoxycarbonyl,benzylcarbonyl, phenyl-C₁₋₄ alkylcarbamoyl, phenylcarbamoyl, phenyl-C₁₋₄alkyl-carbonylamino, benzoylamino, phenyl-C₁₋₄ alkylsulfonyl,phenylsulfonyl, phenyl-C₁₋₄ alkylsulfinyl, phenyl-C₁₋₄alkylsulfonylamino or phenylsulfonylamino which may have 1 to 4substituents selected from the group consisting of C₁₋₄ alkyl groupssuch as methyl, ethyl, propyl, butyl, isopropyl, etc., C₁₋₄ alkoxygroups such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy,etc., halogen atoms such as chlorine, bromine, iodine, etc., hydroxylgroup, benzyloxy group, amino group, mono- or di-C₁₋₄ alkylamino groupsas described above, nitro group, C₁₋₆ alkyl-carbonyl groups as describedabove, benzoyl group, etc. The number of substituents which mayoptionally be substituted on these C₆₋₁₄ aryl groups is suitably about 1to 5.

As the substituents, which C₇₋₁₈ aralkyl, C₆₋₁₄ aryl-C₂₋₁₂ alkenyl,C₆₋₁₄ aryl-C₂₋₁₂ alkynyl, C₃₋₇ cycloalkyl-C₁₋₆ alkyl groups mayoptionally have, use is made of, for example, those similar to thesubstituents which the above-mentioned C₆₋₁₄ aryl groups may optionallyhave. The number of the substituents, which these C₇₋₁₈ aralkyl, C₆₋₁₄aryl-C2-12 alkenyl, C₆₋₁₄ aryl-C₂₋₁₂ alkynyl, C₃₋₇ cycloalkyl-C₁₋₆ alkylmay optionally have, ranges from 1 to 5.

And, R³ and R⁴ may form an optionally substituted heterocyclic group,taken together, with the adjacent nitrogen atom. As the "heterocyclicgroup" of this "optionally substituted heterocyclic group", use is madeof, for example, such heterocyclic groups as those containing, otherthan carbon atoms and one nitrogen atom, optionally 1 to 3 hetero atomse.g. nitrogen, oxygen or sulfur atom, especially 3- to 13-memberedheterocyclic groups. Practically, saturated monocyclic, non-conjugatedunsaturated monocyclic, unsaturated monocyclic, polycyclic and bridgedheterocyclic groups, for example, are employed.

Examples of the saturated monocyclic heterocyclic group include 5- to9-membered saturated monocyclic heterocyclic groups such aspyrrolidinyl, piperidinyl, hexamethyleniminyl, heptamethyleniminyl,oxazolidinyl, morpholinyl, thiazolidinyl, thiomorpholinyl,imidazolidinyl, piperazinyl and homopiperazinyl.

Examples of the non-conjugated unsaturated monocyclic or unsaturatedmonocyclic heterocyclic groups include 5- to 9-membered ones such aspyrrolyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl,1,2,3,6-tetrahydropyridinyl, 2-oxazolidonyl, 2-thiazolidonyl,imidazolyl, pyrazolyl and 1,4,5,6-tetrahydropyrimidinyl.

Examples of the polycyclic heterocyclic group include2,3-dihydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl,2,3,4,5-tetrahydro-1H-1-benzazepinyl, 2,3-dihydro-1H-isoindolyl,1,2,3,4-tetrahydroisoquinolinyl, 2,3,4,5-tetrahydro-1H-2-benzazepinyl,2,3,4,5-tetrahydro-1H-3-benzazepinyl,1,2,3,4,5,6-hexahydro-1-benzazocinyl,1,2,3,4,5,6-hexahydro-2-benzazocinyl,1,2,3,4,5,6-hexahydro-3-benzazocinyl,2,3,4,5,6,7-hexahydro-1H-1-benzazonyl,2,3,4,5,6,7-hexahydro-1H-2-benzazonyl,2,3,4,5,6,7-hexahydro-1H-3-benzazonyl,2,3,4,5,6,7-hexahydro-1H-4-benzazonyl, β-carbolinyl, phenoxazinyl,phenothiazinyl, indolyl, 3H-3-benzazepinyl, 3,4-dihydroquinolinyl,benzimidalyl, 1,4-benzodiazepinyl, etc.

Examples of the bridged heterocyclic group include1,8-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl,1,3,8-triazaspiro[4.5]decanyl, 1,5,9-triazaspiro[5.5]undecanyl,1-oxa-3,9-diazaspiro[5.5]undecanyl, 7-azabicyclo[2.2.1]heptanyl,8-azabicyclo[3.2.11octanyl, 9-azabicyclo[3.3.1]nonanyl, etc.

Preferable examples of "heterocyclic groups" of the "optionallysubstituted heterocyclic group" optionally formed by R³ and R⁴, takentogether with the adjacent nitrogen atom, include the afore-describedsaturated monocyclic heterocyclic groups, polycyclic heterocyclic groupsor bridged heterocyclic groups. Specifically, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, 2,3,4,5-tetrahydro-1H-1-benzazepinyl,2,3,4,5-tetrahydro-1H-2-benzazepinyl,2,3,4,5-tetrahydro-1H-3-benzazepinyl and 1,3,8-triazaspiro[4,5]decanylare preferable, especially, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl and 1,2,3,4-tetrahydroquinolinyl are often employed.

As the "substituent" of "optionally substituted heterocyclic group",which may optionally be formed by the above-mentioned R³ and R⁴, takentogether with the adjacent nitrogen atom, use is made of 1 to 5 groups,preferably 1 or 2 groups, selected from, for example, optionallysubstituted hydrocarbon groups referring to the above-mentioned R¹, R²,R³, R⁴, R⁵ and R⁶, halogen atoms (e.g. fluorine, chlorine, bromine,iodine, etc.), nitro group, cyano group, hydroxyl group, C₁₋₄ alkoxygroups (e.g. methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.),C₁₋₄ alkylthio groups (e.g. methylthio, ethylthio, propylthio,isopropylthio, etc.), aminogroup, mono- or di-C₁₋₄ alkylamino groups(e.g. methyl amino, ethylamino, propylamino, dimethylamino,diethylamino, etc.), C₁₋₄ alkyl-carbonylamino groups (e.g. acetylamino,propionylamino, butyrylamino, etc.), C₁₋₄ alkyl-sulfonylamino groups(e.g. methylsulfonylamino, ethylsulfonylamino, etc.), C₁₋₄alkoxy-carbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, etc.), carboxyl group, formyl group, C₁₋₆alkyl-carbonyl groups (e.g. methylcarbonyl, ethylcarbonyl,propylcarbonyl, etc.), C₁₋₄ alkyl-carbonyloxy groups (e.g. acetyloxy,ethylcarbonyloxy, etc.), ω-oxo-ω-(tetrahydrobenzazepinyl)C₁₋₆ alkylgroups (e.g. 1-oxo-1-(tetrahydrobenzazepinyl)methyl,2-oxo-2-(tetrahydrobenzazepinyl)ethyl,3-oxo-3-(tetrahydrobenzazepinyl)propyl, etc.), optionally substitutedbenzoyl groups (herein, as substituents, use is made of 1 to 3substituents selected from alkyl, for example, methyl, ethyl, etc.,halogen, for example, fluorine, chlorine, bromine, etc., C₁₋₄ alkoxy,for example, methoxy, ethoxy, etc., mono- or di-C₁₋₄ alkylamino, forexample, methylamino, dimethylamino, etc., 5- to 7 -membered cyclicamino groups, for example, piperidino, morpholino, etc., nitro, hydroxy,etc.; practical examples of them being benzoyl, 4-fluorobenzoyl,3,4-dimethoxybenzoyl, etc.), carbamoyl group, mono- or di-C₁₋₄alkylcarbamoyl groups (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), C₁₋₆alkylsulfonyl groups (e.g. methylsulfonyl, ethylsulfonyl,propylsulfonyl, etc.), oxo group, the above-mentioned "heterocyclicgroup" and saturated heterocyclic groups (e.g. pyridyl, pyridinyl,pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, napthylidinyl,benzothiazolyl, benzoxazolyl, furanyl, thiophenyl, etc.). Among them,formyl, C₁₋₄ alkyl-carbonyloxy groups (e.g. acetyloxy, etc.), hydroxylgroup, oxo group, pyridinyl group, optionally substituted benzoyl groups(e.g. benzoyl groups optionally substituted with halogen such asfluorine, chlorine, bromine, etc.), ω-oxo-ω-(tetrahydrobenzazepinyl)C₁₋₆ alkyl groups (e.g. 1-oxo-1-(tetrahydrobenzazepinyl)methyl,2-oxo-2-(tetrahydrobenzazepinyl)ethyl,3-oxo-3-(tetrahydrobenzazepinyl)propyl, etc.), and optionallysubstituted hydrocarbon groups referring to the above-mentioned R¹, R²,R³, R⁴, R⁵, and R⁶ are preferable. Herein, as optionally substitutedhydrocarbon groups referred to in R¹, R², R³, R⁴, R⁵ and R⁶, use isoften made of, for example, or straight-chain or branched C₁₋₁₁ alkylgroups, especially straight-chain or branched C₁₋₇ alkyl groups (e.g.methyl, ethyl, n-pentyl, n-hexyl, etc.) or C₇₋₁₈ aralkyl groups (e.g.phenyl-C₁₋₁₂ alkyl such as phenylmethyl, phenylethyl, phenylpropyl,phenylhexyl, etc., naphtyl-C₁₋₈ alkyl such as α-naphthylmethyl, etc.,diphenyl-C₁₋₈ alkyl such as diphenylmethyl, etc.), especially C₇₋₁₀aralkyl groups (e.g. phenylmethyl, phenylethyl, phenylpropyl, etc.),these alkyl and aralkyl groups having optionally halogen (e.g. fluoro,chloro, bromo, etc.), hydroxyl group, C₁₋₄ alkylenadioxy (e.g.methylenedioxy, etc.).

As "acyl group" of "optionally substituted acyl group" shown by R¹, useis made of, for example, carboxylic acid acyl groups (e.g. formyl, C₁₋₈alkyl-carbonyl or C₆₋₁₄ aryl-carbonyl such as acetyl, propionyl,butyryl, benzoyl, etc.), sulfonic acid acyl groups (e.g. C₁₋₇alkylsulfonyl or C₆₋₁₄ arylsulfonyl such as methanesulfonyl,ethanesulfonyl, propanesulfonyl, benzenesulfonyl, p-toluenesulfonyl,etc.), phosphonic acid acyl groups (e.g. C₁₋₇ alkylphosphonyl or C₆₋₁₄arylphosphonyl such as methanephosphonyl, ethanephosphonyl,propanephosphonyl, benzenephosphonyl, etc.), substituted oxycarbonylgroups (e.g. C₁₋₈ alkoxy-carbonyl or C₇₋₁₈ aralkyloxy-carbonyl such asmethoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl,etc.), heterocycliccarbonyl groups wherein the heterocyclic group is a5- or 6- membered one containing 1 to 3 hetero atoms selected from N,Sand O other than carbon atoms (e.g. pyridylcarbonyl, pyrrolylcarbonyl,quinolylcarbonyl, etc.), carbamoyl group, mono- or di-C₁₋₄alkylcarbamoyl groups (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), etc.Among them, C₁₋₈ alkyl-carbonyl or C₁₋₈ alkoxycarbonyl mentioned aboveis preferable.

As the substituent which these acyl groups may have, use is made of 1 to3, preferably 1 to 2 substituents selected from halogen atoms (e.g.fluorine, chlorine, bromine, iodine, etc.), amino group, mono- ordi-C₁₋₆ alkylamino groups (e.g. methylamino, ethylamino, propylamino,hexylamino, dimethylamino, diethylamino, etc.) and C₁₋₄ alkoxy groups(e.g. methoxy, ethoxy, propoxy, etc.).

The benzene ring shown by ring A may have, besides the groupsrepresented by the formulae ##STR32## further substituents, and as suchsubstituents, use is made of, for example, those mentioned in referenceto C₆₋₁₄ aryl groups of the above-mentioned R¹, R², R³, R⁴, R⁵ and R⁶,the number of them being 1 to 3. Preferable examples of thesubstituents, which such benzene ring may optionally have, include,among others, halogen such as fluoro, chloro, etc., halogeno-C₁₋₃ alkylsuch as trifluoromethyl, etc., C₁₋₃ alkyl such as methyl, etc. and C₁₋₃alkoxy such as methoxy, etc. Especially, fluoro, for example, ispreferable.

The symbol n denotes a whole number of 1 to 10, provided that, in thecase of k=0 and m=2, n is more than 1. Preferably, n ranges from 2 to10, especially from 2 to 8. The symbol k denotes a whole number of 0 to3, and m denotes a whole number of 1 to 8. In other words, the ring##STR33## can form a 4- to 14-membered ring.

X¹ stands for R¹ --N<(R¹ is of the same meaning as defined above),oxygen atom or sulfur atom.

Preferable examples of R¹ include H, straight-chain or branched C₁₋₁₁hydrocarbon groups which may be substituted with the above-mentionedsubstituents (e.g. straight-chain or branched C₁₋₁₁ alkyl such asmethyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl etc., straight-chainor branched C₂₋₄ alkenyl such as vinyl, allyl, 2-butenyl etc.,straight-chain or branched C₂₋₄ alkynyl such as propargyl, 2-butynyletc.), C₇₋₁₈ aralkyl groups which may be substituted with theabove-mentioned substituents (e.g. phenylmethyl, (4-methoxyphenyl)methyl, phenylethyl, phenylpropyl, α-naphthylmethyl etc.), formyl group,C₁₋₈ alkyl-carbonyl (e.g. acetyl, propionyl, butyryl etc.), C₆₋₁₄aryl-carbonyl (e.g. benzoyl etc.), C₁₋₈ alkoxy-carbonyl (e.g.methoxycarbonyl, ethoxycarbonyl etc.), heterocyclic-carbonyl (e.g.pyridylcarbonyl etc.), carbamoyl, mono- or di-C₁₋₄ alkyl-carbamoyl (e.g.methylcarbamoyl, ethylcarbamoyl etc.), etc.; especially H,straight-chain or branched C₁₋₄ alkyl groups (e.g. methyl, ethyl,n-propyl, i-propyl, i-butyl, n-butyl etc.), phenyl-C₁₋₃ alkyl groupswhich may be substituted with 1 to 3 substituents selected from C₁₋₄alkyl, halogen, nitro, cyano, hydroxy, C₁₋₄ alkoxy and C₇₋₁₈ aralkyloxy(e.g. phenylmethyloxy, (4-methoxyphenyl)methyloxy, phenylethyloxy,phenylpropyloxy etc.), naphthyl-C₁₋₃ alkyl (e.g. α-naphtylmethyl, etc.),C₁₋₄ alkyl-carbonyl (e.g. acetyl, propionyl, butyryl, etc.),phenyloxycarbonyl, C₁₋₄ alkoxy-carbonyl (e.g. methoxycarbonyl,ethoxycarbonyl etc.), etc. More preferable examples of R¹ include H,C₁₋₄ alkyl (e.g. methyl, ethyl, propyl, i-propyl, i-butyl, etc.), C₁₋₄alkyl-carbonyl (e.g. acetyl, etc.), phenyl-C₁₋₃ alkyl which may besubstituted with a C₁₋₄ alkoxy (e.g. phenylmethyl,(4-methoxyphenyl)methyl, phenylethyl, etc.); more especially, C₁₋₄ alkylgroup such as i-butyl, etc. or phenyl-C₁₋₃ alkyl which may besubstituted by a C₁₋₄ alkoxy such as methoxy, etc (e.g. phenylmethyl,(4-methoxyphenyl)methyl, phenylethyl).

As R², R⁵ and R⁶, are preferable H, straight-chain or branched C₁₋₃alkyl groups (e.g. methyl, ethyl, n-propyl, i-propyl), phenyl, etc.;especially H is often the case.

Referring to R³ and R⁴, it is preferable that one of them stands for Hor straight-chain or branched C₁₋₄ alkyl groups (e.g. methyl, ethyl,n-propyl, i-propyl, n-butyl) and the other stands for straight-chain orbranched C₁₋₄ alkyl groups, phenyl-C₁₋₃ alkyl groups (e.g. phenylmethyl,phenylethyl, phenylpropyl) or naphthyl-C₁₋₃ alkyl groups (e.g.α-naphthylmethyl). And, as each of R³ and R⁴, also preferable arestraight-chain or branched C₁₋₄ alkyl group which may be substitutedwith a hydroxy (e.g. methyl, ethyl, 2-hydroxyethyl, etc.) or phenyl-C₁₋₃alkyl group which may be substituted with 1 to 3 halogen atoms such asfluorine, chlorine, bromine, etc. (e.g. phenylmethyl, phenylethyl,2-chloro-phenylmethyl, etc.).

And, such cases as forming heterocyclic rings by R³ and R⁴, takentogether with the adjacent nitrogen atom, are also preferable.Preferable examples include optionally substituted pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, 2,3,4,5-tetrahydro-1H-1-benzazepinyl,2,3,4,5-tetrahydro-1H-2-benzazepinyl,2,3,4,5-tetrahydro-1H-3-benzazepinyl, 1,3,8-triazaspiro[4.5]decanyl,etc. especially, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, etc. Especially preferable examples ofthe substituents on the heterocyclic groups include formyl group, C₁₋₄alkyl-carbonyl groups (e.g. acetyl, etc.), hydroxyl group, oxo group,pyridyl group, an optionally substituted benzoyl group (e.g. benzoylgroup which may be substituted with 1 to 3 halogen atoms such asfluorine, chlorine, bromine, etc.), optionally substitutedstraight-chain or branched C₁₋₇ alkyl groups (e.g. methyl, ethyl,n-propyl, i-propyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, which may besubstituted with 1 to 3 substituents such as hydroxy group, 5- or6-membered heterocyclic group containing i to 3 hetero atoms of N, Sand/or O other than carbon atoms such as pyridyl, furyl, thiazol-4-yl,2-methyl-thiazol-4-yl, etc.), an optionally substituted phenyl group(e.g. phenyl group which may be substituted with 1 to 3 substituentssuch as halogen (e.g. fluorine, chlorine, bromine, etc.), hydroxy group,C₁₋₄ alkylene-dioxy (e.g. methylenedioxy, etc.), etc.), optionallysubstituted C₇₋₁₈ aralkyl groups (e.g. phenyl-C₁₋₁₂ alkyl such asphenylmethyl, phenylethyl, phenylpropyl, phenylhexyl, etc.,α-naphthylmethyl, diphenyl-C₁₋₈ alkyl such as diphenylmethyl, etc.,which may be substituted with 1 to 3 substituents such as halogen (e.g.fluorine, chlorine, bromine, etc.), hydroxy group, C₁₋₄ alkylenedioxy(e.g. methylenedioxy, etc.), etc.), ω-oxo-ω-(tetrahydrobenzazepinyl)C₁₋₆ alkyl (e.g. 1-oxo-1-(tetrahydrobenzazepinyl) methyl,2-oxo-2-(tetrahdyrobenzazepinyl) ethyl, 3-oxo-3-(tetrahydrobenzazepinyl)propyl, etc.), the number of them being 1 or 2, preferably 1. As R³ andR⁴, most preferable examples are such cases as forming4-(phenylmethyl)-piperazin-1-yl or4-[(2-methylthiazol-4-yl)methyl]-piperazin-1-yl, taken together with theadjacent nitrogen atom.

Preferable benzene ring shown by ring A is unsubstituted one.

Referring to k and m, the case where k+m denotes a whole number of 2 to6 is preferable, namely the case where the moiety ##STR34## forms a 5-to 9-membered ring. Further, referring to the combination of k and m, itis preferable that, when k is 0, m is 2, 3, 4 or 5; when k is 1, m is 1,2 or 3; and when k is 2, m is 2. More specifically, preferable examplesof the N-containing condensed heterocyclic ring represented by theformula: ##STR35## include 2,3-dihydro-1H-indole,1,2,3,4-tetrahydroquinoline, 2,3,4,5-tetrahydro-1H-1-benzazepine,2,3-dihydro-1H-isoindole, 1,2,3,4-tetrahydroisoquinoline,2,3,4,5-tetrahydro-1H-2-benzazepine, 2,3,4,5-tetrahydro-1H-3-benzazepine, 1,2,3,4,5,6-hexahydro-1-benzazocine ,1,2,3,4,5,6-hexahydro-2-benzazocine, 1,2,3,4,5,6-hexahydro-3-benzazocine, 2,3,4,5,6,7-hexahydro- 1H-1-benzazonine,2,3,4,5,6,7-hexahydro-1H-2-benzazonine,2,3,4,5,6,7-hexahydro-1H-3-benzazonine,2,3,4,5,6,7-hexahydro-1H-4-benzazonine, etc., especially,2,3,4,5-tetrahydro-1H-3-benzazepine, 2,3,4,5-tetrahydro-1H-2-benzazepine, 2,3-dihydro-1H-indole, etc.

Preferable ones of the condensed heterocyclic ring moiety in the aboveformulae shown by the formula: ##STR36## include the N-containingcondensed heterocyclic rings shown by the following formulae: ##STR37##wherein R¹ is of the same meaning as defined above. In the aboveformulae, preferable examples of R¹ include H, C₁₋₄ alkyl groups (e.g.methyl₂ ethyl, n-propyl, i-propyl etc.), phenyl-C₁₋₃ alkyl groups whichmay be substituted by a C₋₄ alkoxy (e.g. phenylmethyl,(4-methoxyphenyl)methyl, phenylethyl, phenylpropyl, etc.) or C₁₋₃alkyl-carbonyl (e.g. acetyl, etc.), etc.

Referring to n, when the group of the formula: ##STR38## does not form aheterocyclic group, it is preferably a whole number of 3 to 8, and, whenthe group forms a heterocyclic group, it is preferably a whole number of2 to 5.

As X¹, R¹ --N< is preferable.

More specifically, the following compounds and salts thereof belongingto the compounds of the formula (I) or salts thereof are preferable.

                                      TABLE 1                                     __________________________________________________________________________     ##STR39##                                                                     ##STR40##                                                                        ##STR41##                                                                         ##STR42##                                                                        ##STR43##                                                                       ##STR44##                                                                        ##STR45##                                                                        ##STR46##                                                                         ##STR47##                                                                        ##STR48##                                           __________________________________________________________________________    1  H   0  2 2  H  H   H                                                                                 ##STR49##                                           2  H   0  2 2  H  H   H                                                                                 ##STR50##                                           3  H   0  2 3  H  H   H                                                                                 ##STR51##                                           4  H   0  2 4  H  H   H                                                                                 ##STR52##                                           5  H   0  2 5  H  H   H                                                                                 ##STR53##                                           6  H   0  2 6  H  H   H                                                                                 ##STR54##                                           7  H   0  2 7  H  H   H                                                                                 ##STR55##                                           8  H   0  2 8  H  H   H                                                                                 ##STR56##                                           9  Ac  0  2 6  H  H   H                                                                                 ##STR57##                                           10 COPh                                                                              0  2 6  H  H   H                                                                                 ##STR58##                                           11 CH.sub.3                                                                          0  2 6  Cl H   H                                                                                 ##STR59##                                           12 CH.sub.2 Ph                                                                       0  2 6  H  OH  H                                                                                 ##STR60##                                           13 Ph  0  2 6  H  OCH.sub.3                                                                         H                                                                                 ##STR61##                                           14 H   0  2 6  F  H   CH.sub.3                                                                          ##STR62##                                           15 CH.sub.2 Ph                                                                       0  2 6  NO.sub.2                                                                         H   H                                                                                 ##STR63##                                           16 H   0  2 6  H  H   H                                                                                 ##STR64##                                           __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________     ##STR65##                                                                        ##STR66##                                                                         ##STR67##                                                                       ##STR68##                                                                       ##STR69##                                                                       ##STR70##                                                                        ##STR71##                                                                         ##STR72##                                                                        ##STR73##                                             __________________________________________________________________________    17 H   0 2 6 H  H   H                                                                                 ##STR74##                                             18 H   0 2 6 H  H   H                                                                                 ##STR75##                                             19 Ac  0 2 6 H  H   H                                                                                 ##STR76##                                             20 H   0 2 6 H  H   H                                                                                 ##STR77##                                             21 H   0 3 1 H  H   H                                                                                 ##STR78##                                             22 H   0 3 2 H  H   H                                                                                 ##STR79##                                             23 H   0 3 3 H  H   H                                                                                 ##STR80##                                             24 H   0 3 4 H  H   H                                                                                 ##STR81##                                             25 H   0 3 5 H  H   H                                                                                 ##STR82##                                             26 H   0 3 6 H  H   H                                                                                 ##STR83##                                             27 H   0 3 7 H  H   H                                                                                 ##STR84##                                             28 H   0 3 8 H  H   H                                                                                 ##STR85##                                             29 Ac  0 3 6 H  H   H                                                                                 ##STR86##                                             30 COPh                                                                              0 3 6 H  H   H                                                                                 ##STR87##                                             31 CH.sub.3                                                                          0 3 6 Cl H   H                                                                                 ##STR88##                                             32 CH.sub.2 Ph                                                                       0 3 6 H  OH  H                                                                                 ##STR89##                                             33 Ph  0 3 6 H  OCH.sub.3                                                                         H                                                                                 ##STR90##                                             34 H   0 3 6 F  H   CH.sub.3                                                                          ##STR91##                                             __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________     ##STR92##                                                                        ##STR93##                                                                         ##STR94##                                                                        ##STR95##                                                                       ##STR96##                                                                        ##STR97##                                                                        ##STR98##                                                                         ##STR99##                                                                        ##STR100##                                          __________________________________________________________________________    35 CH.sub.2 Ph                                                                       0  3 6  NO.sub.2                                                                         H   H                                                                                 ##STR101##                                          36 H   0  3 6  H  H   H                                                                                 ##STR102##                                          37 H   0  3 6  H  H   H                                                                                 ##STR103##                                          38 H   0  3 6  H  H   H                                                                                 ##STR104##                                          39 Ac  0  3 6  H  H   H                                                                                 ##STR105##                                          40 H   0  3 6  H  H   H                                                                                 ##STR106##                                          41 H   0  4 5  H  H   OH                                                                                ##STR107##                                          42 H   0  4 6  H  H   H                                                                                 ##STR108##                                          43 CH.sub.2 Ph                                                                       0  4 6  H  H   H                                                                                 ##STR109##                                          44 CH.sub.3                                                                          0  4 6  F  H   H                                                                                 ##STR110##                                          45 Ac  0  4 7  H  H   CH.sub.3                                                                          ##STR111##                                          46 H   0  5 5  H  H   H                                                                                 ##STR112##                                          47 H   0  5 6  Cl H   H                                                                                 ##STR113##                                          48 H   0  5 6  H  OCH.sub.3                                                                         H                                                                                 ##STR114##                                          49 Ac  0  5 6  H  H   H                                                                                 ##STR115##                                          50 COPh                                                                              0  5 7  H  H   H                                                                                 ##STR116##                                          51 C.sub.2 H.sub.5                                                                   1  1 6  Cl H   H                                                                                 ##STR117##                                          52 CH.sub.2 Ph                                                                       1  1 6  H  OH  H                                                                                 ##STR118##                                          __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     ##STR119##                                                                       ##STR120##                                                                         ##STR121##                                                                      ##STR122##                                                                       ##STR123##                                                                      ##STR124##                                                                       ##STR125##                                                                        ##STR126##                                                                       ##STR127##                                          __________________________________________________________________________    53 Ph   1 2  6 H  OCH.sub.3                                                                         H                                                                                 ##STR128##                                          54 H    1 2  6 F  H   CH.sub.3                                                                          ##STR129##                                          55 CH.sub.2 Ph                                                                        1 2  6 NO.sub.2                                                                         H   H                                                                                 ##STR130##                                          56 H    1 2  6 H  H   H                                                                                 ##STR131##                                          57 H    1 2  6 H  H   H                                                                                 ##STR132##                                          58 H    1 3  6 F  H   H                                                                                 ##STR133##                                          59 Ac   1 3  6 H  H   H                                                                                 ##STR134##                                          60 CH.sub.2 Ph                                                                        1 3  6 H  H   H                                                                                 ##STR135##                                          61 H    2 2  5 H  H   H                                                                                 ##STR136##                                          62 H    2 2  6 H  H   H                                                                                 ##STR137##                                          63 Ac   2 2  6 H  H   H                                                                                 ##STR138##                                          64 CH.sub.3                                                                           2 2  6 H  H   H                                                                                 ##STR139##                                          65 COPh 2 2  6 H  H   H                                                                                 ##STR140##                                          66 CO.sub.2 CH.sub.3                                                                  2 2  7 H  H   H                                                                                 ##STR141##                                          67 Ac   2 2  1 H  H   H                                                                                 ##STR142##                                          68 CH.sub.2 Ph                                                                        2 2  6 H  H   H                                                                                 ##STR143##                                          69 CH.sub.2 Ph                                                                        2 2  7 H  H   H                                                                                 ##STR144##                                          70 CH.sub.2 Ph                                                                        2 2  8 H  H   H                                                                                 ##STR145##                                          __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________     ##STR146##                                                                       ##STR147##                                                                                ##STR148##                                                                      ##STR149##                                                                      ##STR150##                                                                      ##STR151##                                                                        ##STR152##                                                                        ##STR153##                                                                       ##STR154##                                   __________________________________________________________________________    71 CH.sub.2 Ph 2 2 2 H   H   H                                                                                 ##STR155##                                   72 CH.sub.2 Ph 2 2 2 H   H   H                                                                                 ##STR156##                                   73 CH.sub.2 Ph 2 2 2 OCH.sub.3                                                                         OCH.sub.3                                                                         H                                                                                 ##STR157##                                   74 CH.sub.2 Ph 2 2 2 F   H   CH.sub.3                                                                         NH.sub.2                                      75 CH.sub.2 Ph 2 2 2 H   H   H                                                                                 ##STR158##                                   76 CH.sub. 2 Ph                                                                              2 2 2 H   H   CH.sub.3                                                                          ##STR159##                                   77 CH.sub.2 Ph 2 2 2 NO.sub.2                                                                          OH  H                                                                                 ##STR160##                                   78 CH.sub.2 Ph 2 2 2 H   H   H                                                                                 ##STR161##                                   79 CH.sub.2 Ph 2 2 2 H   H   H                                                                                 ##STR162##                                   80                                                                                ##STR163## 2 2 2 OCH.sub.3                                                                         H   H                                                                                 ##STR164##                                   81 Ac          2 2 3 H   H   H                                                                                 ##STR165##                                   82 CH.sub.2 Ph 2 2 3 H   H   H                                                                                 ##STR166##                                   83 CH.sub.2 Ph 2 2 3 H   H   H                                                                                 ##STR167##                                   84 CH.sub.2 Ph 2 2 3 CH.sub.3                                                                          H   H                                                                                 ##STR168##                                   85 CH.sub.2 Ph 2 2 3 Cl  H   H                                                                                 ##STR169##                                   86                                                                                ##STR170## 2 2 3 H   H   H                                                                                 ##STR171##                                   87                                                                                ##STR172## 2 2 3 H   H   H                                                                                 ##STR173##                                   88                                                                                ##STR174## 2 2 3 F   H   H                                                                                 ##STR175##                                   89                                                                                ##STR176## 2 2 3 H   H   H                                                                                 ##STR177##                                   90                                                                                ##STR178## 2 2 3 OCH.sub.3                                                                         H   H                                                                                 ##STR179##                                   __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________     ##STR180##                                                                       ##STR181##                                                                        ##STR182##                                                                      ##STR183##                                                                      ##STR184##                                                                      ##STR185##                                                                        ##STR186##                                                                       ##STR187##                                                                       ##STR188##                                            __________________________________________________________________________    91 CH.sub.2 Ph                                                                       2 2 4 H   H  H                                                                                 ##STR189##                                            92 CH.sub.2 Ph                                                                       2 2 4 CH.sub.3                                                                          OH H                                                                                 ##STR190##                                            93 CH.sub.2 Ph                                                                       2 2 4 OCH.sub.3                                                                         H  H                                                                                 ##STR191##                                            94 CH.sub.2 Ph                                                                       2 2 4 F   H  CH.sub.3                                                                          ##STR192##                                            95 CH.sub.2 Ph                                                                       2 2 4 NO.sub.2                                                                          H  H                                                                                 ##STR193##                                            96 CH.sub.2 Ph                                                                       2 2 5 H   H  H                                                                                 ##STR194##                                            97 CH.sub.2 Ph                                                                       2 2 5 H   H  H                                                                                 ##STR195##                                            98 CH.sub.2 Ph                                                                       2 2 5 CH.sub.3                                                                          H  H                                                                                 ##STR196##                                            99 CH.sub.2 Ph                                                                       2 2 5 Cl  H  OH                                                                                ##STR197##                                            100                                                                              CH.sub.2 Ph                                                                       2 2 5 F   H  H                                                                                 ##STR198##                                            __________________________________________________________________________

                  TABLE 7                                                         ______________________________________                                         ##STR199##                                                                    ##STR200##                                                                         ##STR201##                                                                            ##STR202##                                                                           ##STR203##                                                                         ##STR204##                                                                         ##STR205##                                                                         ##STR206##                                                                        ##STR207##                                                                        ##STR208##                        ______________________________________                                        101  H       0      3    1    H    H   H                                                                                  ##STR209##                        102  H       0      3    2    H    H   H                                                                                  ##STR210##                        103  H       0      3    3    H    H   H                                                                                  ##STR211##                        104  H       0      3    4    H    H   H                                                                                  ##STR212##                        105  H       0      3    5    H    H   H                                                                                  ##STR213##                        106  H       0      3    6    H    H   H                                                                                  ##STR214##                        107  H       0      3    7    H    H   H                                                                                  ##STR215##                        108  H       0      3    8    H    H   H                                                                                  ##STR216##                        109  Ac      0      3    6    H    H   H                                                                                  ##STR217##                        110  COPh    0      3    6    H    H   H                                                                                  ##STR218##                        ______________________________________                                    

                                      TABLE 8                                     __________________________________________________________________________     ##STR219##                                                                       ##STR220##                                                                        ##STR221##                                                                       ##STR222##                                                                       ##STR223##                                                                       ##STR224##                                                                      ##STR225##                                                                        ##STR226##                                                                       ##STR227##                                          __________________________________________________________________________    111                                                                              CH.sub.3                                                                          0  3  6  Cl                                                                              H   H                                                                                 ##STR228##                                          112                                                                              CH.sub.2 Ph                                                                       0  3  6  H OH  H                                                                                 ##STR229##                                          113                                                                              Ph  0  3  6  H OCH.sub.3                                                                         H                                                                                 ##STR230##                                          114                                                                              H   0  3  6  F H   CH.sub.3                                                                          ##STR231##                                          115                                                                              CH.sub.2 Ph                                                                       0  3  6  H H   NO.sub.2                                                                          ##STR232##                                          116                                                                              H   0  3  6  H H   H                                                                                 ##STR233##                                          117                                                                              H   0  3  6  H H   H                                                                                 ##STR234##                                          118                                                                              H   0  3  6  H H   H                                                                                 ##STR235##                                          119                                                                              Ac  0  3  6  H H   H                                                                                 ##STR236##                                          120                                                                              H   0  3  6  H H   H                                                                                 ##STR237##                                          121                                                                              H   0  4  1  H H   H                                                                                 ##STR238##                                          122                                                                              H   0  4  2  H H   H                                                                                 ##STR239##                                          123                                                                              H   0  4  3  H H   H                                                                                 ##STR240##                                          124                                                                              H   0  4  4  H H   H                                                                                 ##STR241##                                          125                                                                              H   0  4  5  H H   H                                                                                 ##STR242##                                          126                                                                              H   0  4  6  H H   H                                                                                 ##STR243##                                          127                                                                              H   0  4  7  H H   H                                                                                 ##STR244##                                          128                                                                              H   0  4  8  H H   H                                                                                 ##STR245##                                          129                                                                              Ac  0  4  6  H H   H                                                                                 ##STR246##                                          __________________________________________________________________________

                                      TABLE 9                                     __________________________________________________________________________     ##STR247##                                                                       ##STR248##                                                                          ##STR249##                                                                      ##STR250##                                                                      ##STR251##                                                                      ##STR252##                                                                       ##STR253##                                                                        ##STR254##                                                                        ##STR255##                                         __________________________________________________________________________    130                                                                              COPh  0 4 6 H  H   H                                                                                  ##STR256##                                         131                                                                              CH.sub.3                                                                            0 4 6 Cl H   H                                                                                  ##STR257##                                         132                                                                              CH.sub.2 Ph                                                                         0 4 6 H  OH  H                                                                                  ##STR258##                                         133                                                                              Ph    0 4 6 H  OCH.sub.3                                                                         H                                                                                  ##STR259##                                         134                                                                              H     0 4 6 F  H   CH.sub.3                                                                           ##STR260##                                         135                                                                              CH.sub.2 Ph                                                                         0 4 6 NO.sub.2                                                                         H   H                                                                                  ##STR261##                                         136                                                                              H     0 4 6 H  H   H                                                                                  ##STR262##                                         137                                                                              H     0 4 6 H  H   H                                                                                  ##STR263##                                         138                                                                              CO.sub.2 Ph                                                                         0 4 6 H  H   H                                                                                  ##STR264##                                         139                                                                              Ac    0 4 6 H  H   H                                                                                  ##STR265##                                         140                                                                              CONHCH.sub.3                                                                        0 4 6 H  H   H                                                                                  ##STR266##                                         141                                                                              H     0 5 4 H  H   H                                                                                  ##STR267##                                         142                                                                              H     0 5 5 H  H   H                                                                                  ##STR268##                                         143                                                                              H     0 5 6 H  H   H                                                                                  ##STR269##                                         144                                                                              H     0 5 6 H  H   H                                                                                  ##STR270##                                         145                                                                              CH.sub.3                                                                            0 5 6 H  OH  H                                                                                  ##STR271##                                         146                                                                              CH.sub.2 Ph                                                                         0 5 6 H  OCH.sub.3                                                                         H                                                                                  ##STR272##                                         147                                                                              Ac    0 5 6 H  H   Cl                                                                                 ##STR273##                                         148                                                                              CONHCH.sub.3                                                                        0 5 6 F  H   H                                                                                  ##STR274##                                         149                                                                              H     0 5 7 H  OCH.sub.3                                                                         OCH.sub.3                                                                          ##STR275##                                         __________________________________________________________________________

                  TABLE 10                                                        ______________________________________                                         ##STR276##                                                                         ##STR277##                                                                            ##STR278##                                                                          ##STR279##                                                                        ##STR280##                                                                        ##STR281##                                                                        ##STR282##                                                                          ##STR283##                                                                         ##STR284##                         ______________________________________                                        150  COPh    0     5   8   H   H     H                                                                                   ##STR285##                         151  H       0     2   3   Cl  H     H                                                                                   ##STR286##                         152  CH.sub.2 Ph                                                                           0     2   4   H   OH    H                                                                                   ##STR287##                         153  Ph      0     2   6   H   OCH.sub.3                                                                           H                                                                                   ##STR288##                         154  H       0     2   6   F   H     CH.sub.3                                                                            ##STR289##                         155  CH.sub.2 Ph                                                                           0     2   6   H   H     H                                                                                   ##STR290##                         156  CH.sub.2 Ph                                                                           1     2   2   H   H     H                                                                                   ##STR291##                         157  CH.sub.2 Ph                                                                           1     2   3   H   H     H                                                                                   ##STR292##                         158  CH.sub.2 Ph                                                                           1     2   4   H   OH    H                                                                                   ##STR293##                         159  Ac      1     2   5   H   OH.sub.3                                                                            H                                                                                   ##STR294##                         160  H       1     2   6   H   H     H                                                                                   ##STR295##                         161  H       1     3   2   H   H     H                                                                                   ##STR296##                         162  H       1     3   2   H   H     H                                                                                   ##STR297##                         ______________________________________                                    

                                      TABLE 11                                    __________________________________________________________________________     ##STR298##                                                                       ##STR299##                                                                         ##STR300##                                                                      ##STR301##                                                                      ##STR302##                                                                      ##STR303##                                                                       ##STR304##                                                                        ##STR305##                                                                        ##STR306##                                          __________________________________________________________________________    163                                                                              H    1 3 3 H  H   H                                                                                  ##STR307##                                          164                                                                              H    1 3 4 H  H   H                                                                                  ##STR308##                                          165                                                                              H    1 3 5 H  H   H                                                                                  ##STR309##                                          166                                                                              H    1 3 6 H  H   H                                                                                  ##STR310##                                          167                                                                              H    1 3 7 H  H   H                                                                                  ##STR311##                                          168                                                                              H    1 3 8 H  H   H                                                                                  ##STR312##                                          169                                                                              Ac   1 3 6 H  H   H                                                                                  ##STR313##                                          170                                                                              COPh 1 3 6 H  H   H                                                                                  ##STR314##                                          171                                                                              CH.sub.3                                                                           1 3 6 Cl H   H                                                                                  ##STR315##                                          172                                                                              CO.sub.2 CH.sub.3                                                                  1 3 6 H  OH  H                                                                                  ##STR316##                                          173                                                                              Ph   1 3 6 H  OCH.sub.3                                                                         H                                                                                  ##STR317##                                          174                                                                              H    1 3 4 F  H   CH.sub.3                                                                           ##STR318##                                          175                                                                              C.sub.2 H.sub.5                                                                    1 3 5 NO.sub.2                                                                         H   H                                                                                  ##STR319##                                          176                                                                              H    1 3 6 H  H   CH.sub.3                                                                           ##STR320##                                          177                                                                              H    1 3 6 H  H   OCH.sub.3                                                                          ##STR321##                                          178                                                                              H    1 3 6 H  H   H                                                                                  ##STR322##                                          179                                                                              Ac   1 3 6 H  H   H                                                                                  ##STR323##                                          180                                                                              H    1 3 6 H  H   H                                                                                  ##STR324##                                          181                                                                              CH.sub.2 Ph                                                                        1 3 5 H  H   H                                                                                  ##STR325##                                          __________________________________________________________________________

                                      TABLE 12                                    __________________________________________________________________________     ##STR326##                                                                       ##STR327##                                                                                 ##STR328##                                                                      ##STR329##                                                                      ##STR330##                                                                      ##STR331##                                                                      ##STR332##                                                                        ##STR333##                                                                        ##STR334##                                   __________________________________________________________________________    182                                                                              CH.sub.2 Ph  1 3 5 H H   H                                                                                  ##STR335##                                   183                                                                              CH.sub.2 Ph  1 3 6 H H   H                                                                                  ##STR336##                                   184                                                                              CH.sub.2 Ph  1 3 7 H H   H                                                                                  ##STR337##                                   185                                                                              CH.sub.2 Ph  1 3 8 H H   H                                                                                  ##STR338##                                   186                                                                              CH.sub.2 Ph  1 3 2 H H   H                                                                                  ##STR339##                                   187                                                                              CH.sub.2 Ph  1 3 2 H H   H                                                                                  ##STR340##                                   188                                                                              CH.sub.2 Ph  1 3 2 H OCH.sub.3                                                                         OCH.sub.3                                                                          ##STR341##                                   189                                                                               ##STR342##  1 3 2 H H   H                                                                                  ##STR343##                                   190                                                                               ##STR344##  1 3 2 H H   H                                                                                  ##STR345##                                   191                                                                              CH.sub.2 Ph  1 3 3 H H   H                                                                                  ##STR346##                                   192                                                                              CH.sub.2 Ph  1 3 3 H H   H                                                                                  ##STR347##                                   193                                                                              CH.sub.2 Ph  1 3 3 H OCH.sub.3                                                                         H                                                                                  ##STR348##                                   194                                                                               ##STR349##  1 3 3 H H   CH.sub.3                                                                           ##STR350##                                   195                                                                               ##STR351##  1 3 3 H H   NO.sub.2                                                                           ##STR352##                                   196                                                                              CH.sub.2 Ph  1 3 4 H H   H                                                                                  ##STR353##                                   197                                                                              CH.sub.2 Ph  1 3 4 H H   H                                                                                  ##STR354##                                   198                                                                              CH.sub.2 Ph  1 3 4 H H   H                                                                                  ##STR355##                                   199                                                                               ##STR356##  1 3 4 H CH.sub.3                                                                          CH.sub.3                                                                           ##STR357##                                   200                                                                               ##STR358##  1 3 4 H H   OCH.sub.3                                                                          ##STR359##                                   __________________________________________________________________________

                  TABLE 13                                                        ______________________________________                                         ##STR360##                   201                                              ##STR361##                   202                                              ##STR362##                   203                                              ##STR363##                   204                                              ##STR364##                   205                                             ______________________________________                                    

                                      TABLE 14                                    __________________________________________________________________________     ##STR365##                                                                    ##STR366##                                                                       ##STR367##                                                                                  ##STR368##                                                                      ##STR369##                                                                      ##STR370##                                                                      ##STR371##                                                                      ##STR372##                                                                      ##STR373##                                                                      ##STR374##                                      __________________________________________________________________________    206                                                                              NH            2 2 2 H H H                                                                                ##STR375##                                      207                                                                              NAc           2 2 2 H H H                                                                                ##STR376##                                      208                                                                              NCOPh         2 2 2 H H H                                                                                ##STR377##                                      209                                                                              NCH.sub.3     2 2 2 H H H                                                                                ##STR378##                                      210                                                                              NC.sub.2 H.sub.5                                                                            2 2 2 H H H                                                                                ##STR379##                                      211                                                                              NCH(CH.sub.3).sub.2                                                                         2 2 2 H H H                                                                                ##STR380##                                      212                                                                              NC.sub.3 H.sub.7                                                                            2 2 2 H H H                                                                                ##STR381##                                      213                                                                              NCHPh.sub.2   2 2 2 H H H                                                                                ##STR382##                                      214                                                                              NCONHCH.sub.3 2 2 2 H H H                                                                                ##STR383##                                      215                                                                              NSO.sub.2 Ph  2 2 2 H H H                                                                                ##STR384##                                      216                                                                              NSO.sub.2 CH.sub.3                                                                          2 2 2 H H H                                                                                ##STR385##                                      217                                                                               ##STR386##   2 2 2 H H H                                                                                ##STR387##                                      218                                                                               ##STR388##   2 2 2 H H H                                                                                ##STR389##                                      219                                                                               ##STR390##   2 2 2 H H H                                                                                ##STR391##                                      220                                                                               ##STR392##   2 2 2 H H H                                                                                ##STR393##                                      __________________________________________________________________________

                                      TABLE 15                                    __________________________________________________________________________     ##STR394##                                                                       ##STR395##                                                                                   ##STR396##                                                                      ##STR397##                                                                      ##STR398##                                                                      ##STR399##                                                                      ##STR400##                                                                      ##STR401##                                                                      ##STR402##                                     __________________________________________________________________________    221                                                                               ##STR403##    2 2 2 H H H                                                                                ##STR404##                                     222                                                                               ##STR405##    2 2 2 H H H                                                                                ##STR406##                                     223                                                                               ##STR407##    2 2 2 H H H                                                                                ##STR408##                                     224                                                                               ##STR409##    2 2 2 H H H                                                                                ##STR410##                                     225                                                                               ##STR411##    2 2 2 H H H                                                                                ##STR412##                                     226                                                                               ##STR413##    2 2 2 H H H                                                                                ##STR414##                                     227                                                                               ##STR415##    2 2 2 H H H                                                                                ##STR416##                                     228                                                                               ##STR417##    2 2 2 H H H                                                                                ##STR418##                                     229                                                                               ##STR419##    2 2 2 H H H                                                                                ##STR420##                                     230                                                                               ##STR421##    2 2 2 H H H                                                                                ##STR422##                                     231                                                                              NH             2 2 2 H H H                                                                                ##STR423##                                     232                                                                              NH             2 2 2 H H H                                                                                ##STR424##                                     233                                                                              NH             2 2 2 H H H                                                                                ##STR425##                                     234                                                                              NH             2 2 2 H H H                                                                                ##STR426##                                     235                                                                              NH             2 2 2 H H H                                                                                ##STR427##                                     236                                                                              NH             2 2 2 H H H                                                                                ##STR428##                                     237                                                                              NH             2 2 2 H H H                                                                                ##STR429##                                     238                                                                              NH             2 2 2 H H H                                                                                ##STR430##                                     239                                                                              NH             2 2 2 H H H                                                                                ##STR431##                                     240                                                                              NH             2 2 2 H H H                                                                                ##STR432##                                     __________________________________________________________________________

                                      TABLE 16                                    __________________________________________________________________________     ##STR433##                                                                       ##STR434##                                                                         ##STR435##                                                                      ##STR436##                                                                      ##STR437##                                                                      ##STR438##                                                                      ##STR439##                                                                      ##STR440##                                                                      ##STR441##                                               __________________________________________________________________________    241                                                                              NH   2 2 2 H H H                                                                                ##STR442##                                               242                                                                              NH   2 2 2 H H H                                                                                ##STR443##                                               243                                                                              NH   2 2 2 H H H                                                                                ##STR444##                                               244                                                                              NH   2 2 2 H H H                                                                                ##STR445##                                               245                                                                              NH   2 2 2 H H H                                                                                ##STR446##                                               246                                                                              NH   2 2 2 H H H                                                                                ##STR447##                                               247                                                                              NH   2 2 2 H H H                                                                                ##STR448##                                               248                                                                              NH   2 2 2 H H H                                                                                ##STR449##                                               249                                                                              NH   2 2 2 H H H                                                                                ##STR450##                                               250                                                                              NH   2 2 2 H H H                                                                                ##STR451##                                               251                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR452##                                               252                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR453##                                               253                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR454##                                               254                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR455##                                               255                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR456##                                               256                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR457##                                               257                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR458##                                               258                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR459##                                               259                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR460##                                               260                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR461##                                               __________________________________________________________________________

                                      TABLE 17                                    __________________________________________________________________________     ##STR462##                                                                       ##STR463##                                                                         ##STR464##                                                                      ##STR465##                                                                      ##STR466##                                                                      ##STR467##                                                                      ##STR468##                                                                      ##STR469##                                                                      ##STR470##                                               __________________________________________________________________________    261                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR471##                                               262                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR472##                                               263                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR473##                                               264                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR474##                                               265                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR475##                                               266                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR476##                                               267                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR477##                                               268                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR478##                                               269                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR479##                                               270                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR480##                                               271                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR481##                                               272                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR482##                                               273                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR483##                                               274                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR484##                                               275                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR485##                                               276                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR486##                                               277                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR487##                                               278                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR488##                                               279                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR489##                                               280                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H H                                                                                ##STR490##                                               __________________________________________________________________________

                                      TABLE 18                                    __________________________________________________________________________     ##STR491##                                                                       ##STR492##                                                                         ##STR493##                                                                      ##STR494##                                                                      ##STR495##                                                                      ##STR496##                                                                      ##STR497##                                                                      ##STR498##                                                                      ##STR499##                                               __________________________________________________________________________    281                                                                              NAc  2 2 2 H H H                                                                                ##STR500##                                               282                                                                              NAc  2 2 2 H H H                                                                                ##STR501##                                               283                                                                              NAc  2 2 2 H H H                                                                                ##STR502##                                               284                                                                              NAc  2 2 2 H H H                                                                                ##STR503##                                               285                                                                              NAc  2 2 2 H H H                                                                                ##STR504##                                               286                                                                              NAc  2 2 2 H H H                                                                                ##STR505##                                               287                                                                              NAc  2 2 2 H H H                                                                                ##STR506##                                               288                                                                              NAc  2 2 2 H H H                                                                                ##STR507##                                               289                                                                              NAc  2 2 2 H H H                                                                                ##STR508##                                               290                                                                              NAc  2 2 2 H H H                                                                                ##STR509##                                               291                                                                              NAc  2 2 2 H H H                                                                                ##STR510##                                               292                                                                              NAc  2 2 2 H H H                                                                                ##STR511##                                               293                                                                              NAc  2 2 2 H H H                                                                                ##STR512##                                               294                                                                              NAc  2 2 2 H H H                                                                                ##STR513##                                               295                                                                              NAc  2 2 2 H H H                                                                                ##STR514##                                               296                                                                              NAc  2 2 2 H H H                                                                                ##STR515##                                               297                                                                              NAc  2 2 2 H H H                                                                                ##STR516##                                               298                                                                              NAc  2 2 2 H H H                                                                                ##STR517##                                               299                                                                              NAc  2 2 2 H H H                                                                                ##STR518##                                               300                                                                              NAc  2 2 2 H H H                                                                                ##STR519##                                               __________________________________________________________________________

                                      TABLE 19                                    __________________________________________________________________________     ##STR520##                                                                       ##STR521##                                                                         ##STR522##                                                                      ##STR523##                                                                      ##STR524##                                                                      ##STR525##                                                                      ##STR526##                                                                      ##STR527##                                                                      ##STR528##                                               __________________________________________________________________________    301                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR529##                                               302                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR530##                                               303                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR531##                                               304                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR532##                                               305                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR533##                                               306                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR534##                                               307                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR535##                                               308                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR536##                                               309                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR537##                                               310                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR538##                                               311                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR539##                                               312                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR540##                                               313                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR541##                                               314                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR542##                                               315                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR543##                                               316                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR544##                                               317                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR545##                                               318                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR546##                                               319                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR547##                                               320                                                                              NCH.sub.3                                                                          2 2 2 H H H                                                                                ##STR548##                                               __________________________________________________________________________

                                      TABLE 20                                    __________________________________________________________________________     ##STR549##                                                                       ##STR550##                                                                       ##STR551##                                                                       ##STR552##                                                                      ##STR553##                                                                        ##STR554##                                                                      ##STR555##                                                                        ##STR556##                                                                      ##STR557##                                            __________________________________________________________________________    321                                                                              NH 2  2 2   H H   H                                                                                ##STR558##                                            322                                                                              NH 2  2 2   H H   H                                                                                ##STR559##                                            323                                                                              NH 2  2 2   H H   H                                                                                ##STR560##                                            324                                                                              NH 2  2 2   H H   H                                                                                ##STR561##                                            325                                                                              NH 2  2 2   H H   H                                                                                ##STR562##                                            326                                                                              NH 2  2 2   H H   H                                                                                ##STR563##                                            327                                                                              NH 2  2 2   H H   H                                                                                ##STR564##                                            328                                                                              NH 2  2 2   H H   H                                                                                ##STR565##                                            329                                                                              NH 2  2 2   H H   H                                                                                ##STR566##                                            330                                                                              NH 2  2 2   H H   H                                                                                ##STR567##                                            331                                                                              NH 2  2 2   H H   H                                                                                ##STR568##                                            332                                                                              NH 2  2 2   H H   H                                                                                ##STR569##                                            333                                                                              NH 2  2 2   H H   H                                                                                ##STR570##                                            334                                                                              NH 2  2 2   H H   H                                                                                ##STR571##                                            335                                                                              NH 2  2 2   H H   H NH.sub.2                                               336                                                                              NH 2  2 2   H H   H                                                                                ##STR572##                                            337                                                                              NH 2  2 2   H H   H                                                                                ##STR573##                                            338                                                                              NH 2  2 2   H H   H                                                                                ##STR574##                                            339                                                                              NH 2  2 2   H H   H                                                                                ##STR575##                                            340                                                                              NH 2  2 2   H H   H                                                                                ##STR576##                                            __________________________________________________________________________

                                      TABLE 21                                    __________________________________________________________________________     ##STR577##                                                                       ##STR578##                                                                       ##STR579##                                                                       ##STR580##                                                                      ##STR581##                                                                        ##STR582##                                                                      ##STR583##                                                                        ##STR584##                                                                      ##STR585##                                            __________________________________________________________________________    341                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR586##                                            342                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR587##                                            343                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR588##                                            344                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR589##                                            345                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR590##                                            346                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR591##                                            347                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR592##                                            348                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR593##                                            349                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR594##                                            350                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR595##                                            351                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR596##                                            352                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR597##                                            353                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR598##                                            354                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR599##                                            355                                                                              NAc                                                                              2  2 2   H H   H NH.sub.2                                               356                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR600##                                            357                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR601##                                            358                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR602##                                            359                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR603##                                            360                                                                              NAc                                                                              2  2 2   H H   H                                                                                ##STR604##                                            __________________________________________________________________________

                                      TABLE 22                                    __________________________________________________________________________     ##STR605##                                                                       ##STR606##                                                                        ##STR607##                                                                      ##STR608##                                                                      ##STR609##                                                                        ##STR610##                                                                      ##STR611##                                                                        ##STR612##                                                                      ##STR613##                                            __________________________________________________________________________    361                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR614##                                            362                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR615##                                            363                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR616##                                            364                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR617##                                            365                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR618##                                            366                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR619##                                            367                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR620##                                            368                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR621##                                            369                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR622##                                            370                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR623##                                            371                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR624##                                            372                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR625##                                            373                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR626##                                            374                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR627##                                            375                                                                              NCH.sub.3                                                                         2 2 2   H H   H NH.sub.2                                               376                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR628##                                            377                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR629##                                            378                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR630##                                            379                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR631##                                            380                                                                              NCH.sub.3                                                                         2 2 2   H H   H                                                                                ##STR632##                                            __________________________________________________________________________

                                      TABLE 23                                    __________________________________________________________________________     ##STR633##                                                                       ##STR634##                                                                         ##STR635##                                                                      ##STR636##                                                                       ##STR637##                                                                      ##STR638##                                                                       ##STR639##                                                                      ##STR640##                                                                       ##STR641##                                            __________________________________________________________________________    381                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR642##                                            382                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR643##                                            383                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR644##                                            384                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR645##                                            385                                                                              NCH.sub. 2 Ph                                                                      2 2  2 H  H H                                                                                 ##STR646##                                            386                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR647##                                            387                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR648##                                            388                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR649##                                            389                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR650##                                            390                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR651##                                            391                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR652##                                            392                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR653##                                            393                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR654##                                            394                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR655##                                            395                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H  NH.sub.2                                               396                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR656##                                            397                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR657##                                            398                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR658##                                            399                                                                              NCH.sub.2 Ph                                                                       2 2  2 H  H H                                                                                 ##STR659##                                            400                                                                              NCH.sub. 2 Ph                                                                      2 2  2 H  H H                                                                                 ##STR660##                                            __________________________________________________________________________

                                      TABLE 24                                    __________________________________________________________________________     ##STR661##                                                                       ##STR662##                                                                         ##STR663##                                                                      ##STR664##                                                                       ##STR665##                                                                      ##STR666##                                                                       ##STR667##                                                                      ##STR668##                                                                       ##STR669##                                            __________________________________________________________________________    401                                                                              NCH.sub.2 Ph                                                                       2 2  3 H  H H                                                                                 ##STR670##                                            402                                                                              NCH.sub.2 Ph                                                                       2 2  3 H  H H                                                                                 ##STR671##                                            403                                                                              NCH.sub.2 Ph                                                                       2 2  3 H  H H                                                                                 ##STR672##                                            404                                                                              NCH.sub.2 Ph                                                                       2 2  3 H  H H                                                                                 ##STR673##                                            405                                                                              NCH.sub.2 Ph                                                                       2 2  3 H  H H                                                                                 ##STR674##                                            406                                                                              NCH.sub.3                                                                          2 2  3 H  H H                                                                                 ##STR675##                                            407                                                                              NCH.sub.3                                                                          2 2  3 H  H H                                                                                 ##STR676##                                            408                                                                              NCH.sub.3                                                                          2 2  3 H  H H                                                                                 ##STR677##                                            409                                                                              NCH.sub.3                                                                          2 2  3 H  H H                                                                                 ##STR678##                                            410                                                                              NCH.sub.3                                                                          2 2  3 H  H H                                                                                 ##STR679##                                            411                                                                              NH   2 2  3 H  H H                                                                                 ##STR680##                                            412                                                                              NH   2 2  3 H  H H                                                                                 ##STR681##                                            413                                                                              NH   2 2  3 H  H H                                                                                 ##STR682##                                            414                                                                              NH   2 2  3 H  H H                                                                                 ##STR683##                                            415                                                                              NH   2 2  3 H  H H                                                                                 ##STR684##                                            416                                                                              NAc  2 2  3 H  H H                                                                                 ##STR685##                                            417                                                                              NAc  2 2  3 H  H H                                                                                 ##STR686##                                            418                                                                              NAc  2 2  3 H  H H                                                                                 ##STR687##                                            419                                                                              NAc  2 2  3 H  H H                                                                                 ##STR688##                                            420                                                                              NAc  2 2  3 H  H H                                                                                 ##STR689##                                            __________________________________________________________________________

                                      TABLE 25                                    __________________________________________________________________________     ##STR690##                                                                       ##STR691##                                                                         ##STR692##                                                                        ##STR693##                                                                      ##STR694##                                                                        ##STR695##                                                                      ##STR696##                                                                        ##STR697##                                                                      ##STR698##                                         __________________________________________________________________________    421                                                                              NH   2   2 1   H H   H                                                                                ##STR699##                                         422                                                                              NAc  2   2 1   H H   H                                                                                ##STR700##                                         423                                                                              NCH.sub.3                                                                          2   2 1   H H   H                                                                                ##STR701##                                         424                                                                              NCH.sub.2 Ph                                                                       2   2 1   H H   H                                                                                ##STR702##                                         425                                                                              NAc  2   2 1   H H   H                                                                                ##STR703##                                         426                                                                              NCH.sub.2 Ph                                                                       2   2 1   H H   H                                                                                ##STR704##                                         427                                                                              NH   2   2 3   H H   H                                                                                ##STR705##                                         428                                                                              NAc  2   2 3   H H   H                                                                                ##STR706##                                         429                                                                              NCH.sub.3                                                                          2   2 3   H H   H                                                                                ##STR707##                                         430                                                                              NCH.sub.2 Ph                                                                       2   2 3   H H   H                                                                                ##STR708##                                         431                                                                              NAc  2   2 3   H H   H                                                                                ##STR709##                                         432                                                                              NCH.sub.2 Ph                                                                       2   2 3   H H   H                                                                                ##STR710##                                         433                                                                              NH   2   2 4   H H   H                                                                                ##STR711##                                         434                                                                              NAc  2   2 4   H H   H                                                                                ##STR712##                                         435                                                                              NCH.sub.3                                                                          2   2 4   H H   H                                                                                ##STR713##                                         436                                                                              NCH.sub.2 Ph                                                                       2   2 4   H H   H                                                                                ##STR714##                                         437                                                                              NAc  2   2 4   H H   H                                                                                ##STR715##                                         438                                                                              NCH.sub.2 Ph                                                                       2   2 4   H H   H                                                                                ##STR716##                                         439                                                                              NAc  2   2 1   H H   H                                                                                ##STR717##                                         440                                                                              NH   2   2 1   H H   H                                                                                ##STR718##                                         __________________________________________________________________________

                                      TABLE 26                                    __________________________________________________________________________     ##STR719##                                                                       ##STR720##                                                                          ##STR721##                                                                       ##STR722##                                                                      ##STR723##                                                                        ##STR724##                                                                      ##STR725##                                                                        ##STR726##                                                                      ##STR727##                                         __________________________________________________________________________    441                                                                              NCH.sub.2 Ph                                                                        0  3 2   H H   H                                                                                ##STR728##                                         442                                                                              NH    0  3 2   H H   H                                                                                ##STR729##                                         443                                                                              NCO.sub.2 C.sub.2 H.sub.5                                                           0  3 2   H H   H                                                                                ##STR730##                                         444                                                                              NAc   0  3 2   H H   H                                                                                ##STR731##                                         445                                                                              NH    0  3 1   H H   H                                                                                ##STR732##                                         446                                                                              NCH.sub.2 Ph                                                                        0  4 2   H H   H                                                                                ##STR733##                                         447                                                                              NH    0  4 2   H H   H                                                                                ##STR734##                                         448                                                                              NCO.sub.2 C.sub.2 H.sub.5                                                           0  4 2   H H   H                                                                                ##STR735##                                         449                                                                              NAc   0  4 2   H H   H                                                                                ##STR736##                                         450                                                                              NH    0  4 1   H H   H                                                                                ##STR737##                                         451                                                                              NCH.sub.2 Ph                                                                        0  5 2   H H   H                                                                                ##STR738##                                         452                                                                              NH    0  5 2   H H   H                                                                                ##STR739##                                         453                                                                              NCO.sub.2 C.sub.2 H.sub.5                                                           0  5 2   H H   H                                                                                ##STR740##                                         454                                                                              NAc   0  5 2   H H   H                                                                                ##STR741##                                         455                                                                              NH    0  5 1   H H   H                                                                                ##STR742##                                         456                                                                              NCH.sub.2 Ph                                                                        1  3 2   H H   H                                                                                ##STR743##                                         457                                                                              NH    1  3 2   H H   H                                                                                ##STR744##                                         458                                                                              NCO.sub.2 C.sub.2 H.sub.5                                                           1  3 2   H H   H                                                                                ##STR745##                                         459                                                                              NAc   1  3 2   H H   H                                                                                ##STR746##                                         460                                                                              NH    1  3 1   H H   H                                                                                ##STR747##                                         __________________________________________________________________________

                                      TABLE 27                                    __________________________________________________________________________     ##STR748##                                                                    ##STR749##                                                                       ##STR750##                                                                          ##STR751##                                                                       ##STR752##                                                                      ##STR753##                                                                        ##STR754##                                                                      ##STR755##                                                                        ##STR756##                                                                      ##STR757##                                         __________________________________________________________________________    461                                                                              NCH.sub.2 Ph                                                                        0  2 2   H H   H                                                                                ##STR758##                                         462                                                                              NH    0  2 2   H H   H                                                                                ##STR759##                                         463                                                                              NCH.sub.3                                                                           0  2 2   H H   H                                                                                ##STR760##                                         464                                                                              NAc   0  2 2   H H   H                                                                                ##STR761##                                         465                                                                              NCO.sub.2 C.sub.2 H.sub.5                                                           0  2 2   H H   H                                                                                ##STR762##                                         466                                                                              NCH.sub.2 Ph                                                                        0  3 2   H H   H                                                                                ##STR763##                                         467                                                                              NH    0  3 2   H H   H                                                                                ##STR764##                                         468                                                                              NCH.sub.3                                                                           0  3 2   H H   H                                                                                ##STR765##                                         469                                                                              NAc   0  3 2   H H   H                                                                                ##STR766##                                         470                                                                              NCO.sub.2 C.sub.2 H.sub.5                                                           0  3 2   H H   H                                                                                ##STR767##                                         471                                                                              NCH.sub.2 Ph                                                                        0  4 2   H H   H                                                                                ##STR768##                                         472                                                                              NH    0  4 2   H H   H                                                                                ##STR769##                                         473                                                                              NCH.sub.3                                                                           0  4 2   H H   H                                                                                ##STR770##                                         474                                                                              NAc   0  4 2   H H   H                                                                                ##STR771##                                         475                                                                              NCO.sub.2 C.sub.2 H.sub.5                                                           0  4 2   H H   H                                                                                ##STR772##                                         476                                                                              NCH.sub.2 Ph                                                                        1  3 2   H H   H                                                                                ##STR773##                                         477                                                                              NH    1  3 2   H H   H                                                                                ##STR774##                                         478                                                                              NCH.sub.3                                                                           1  3 2   H H   H                                                                                ##STR775##                                         479                                                                              NAc   1  3 2   H H   H                                                                                ##STR776##                                         480                                                                              NCO.sub.2 C.sub.2 H.sub.5                                                           1  3 2   H H   H                                                                                ##STR777##                                         __________________________________________________________________________

                                      TABLE 28                                    __________________________________________________________________________     ##STR778##                                                                       ##STR779##                                                                          ##STR780##                                                                       ##STR781##                                                                      ##STR782##                                                                        ##STR783##                                                                      ##STR784##                                                                        ##STR785##                                                                      ##STR786##                                         __________________________________________________________________________    481                                                                              NCH.sub.2 Ph                                                                        1  2 2   H H   H                                                                                ##STR787##                                         482                                                                              NH    1  2 2   H H   H                                                                                ##STR788##                                         483                                                                              NCH.sub.3                                                                           1  2 2   H H   H                                                                                ##STR789##                                         484                                                                              NAc   1  2 2   H H   H                                                                                ##STR790##                                         485                                                                              NCO.sub.2 C.sub.2 H.sub.5                                                           1  2 2   H H   H                                                                                ##STR791##                                         486                                                                              O     0  2 2   H H   H                                                                                ##STR792##                                         487                                                                              O     0  2 2   H H   H                                                                                ##STR793##                                         488                                                                              O     0  2 2   H H   H                                                                                ##STR794##                                         489                                                                              O     0  3 2   H H   H                                                                                ##STR795##                                         490                                                                              O     0  3 2   H H   H                                                                                ##STR796##                                         491                                                                              O     0  4 2   H H   H                                                                                ##STR797##                                         492                                                                              O     0  4 2   H H   H                                                                                ##STR798##                                         493                                                                              O     0  2 1   H H   H                                                                                ##STR799##                                         494                                                                              S     0  2 2   H H   H                                                                                ##STR800##                                         495                                                                              S     0  2 2   H H   H                                                                                ##STR801##                                         496                                                                              S     0  3 2   H H   H                                                                                ##STR802##                                         497                                                                              S     0  3 2   H H   H                                                                                ##STR803##                                         498                                                                              S     0  4 2   H H   H                                                                                ##STR804##                                         499                                                                              S     0  4 2   H H   H                                                                                ##STR805##                                         500                                                                              S     0  3 1   H H   H                                                                                ##STR806##                                         __________________________________________________________________________

                                      TABLE 29                                    __________________________________________________________________________     ##STR807##                                                                       ##STR808##                                                                         ##STR809##                                                                        ##STR810##                                                                      ##STR811##                                                                        ##STR812##                                                                      ##STR813##                                                                        ##STR814##                                                                      ##STR815##                                         __________________________________________________________________________    501                                                                              NAc  0   2 1   H H   H                                                                                ##STR816##                                         502                                                                              NH   0   2 1   H H   H                                                                                ##STR817##                                         503                                                                              NCH.sub.3                                                                          0   2 1   H H   H                                                                                ##STR818##                                         504                                                                              NCH.sub.2 Ph                                                                       0   2 1   H H   H                                                                                ##STR819##                                         505                                                                              NH   0   2 1   H H   H                                                                                ##STR820##                                         506                                                                              NAc  0   3 1   H H   H                                                                                ##STR821##                                         507                                                                              NH   0   3 1   H H   H                                                                                ##STR822##                                         508                                                                              NCH.sub.3                                                                          0   3 1   H H   H                                                                                ##STR823##                                         509                                                                              NCH.sub.2 Ph                                                                       0   3 1   H H   H                                                                                ##STR824##                                         510                                                                              NH   0   3 1   H H   H                                                                                ##STR825##                                         511                                                                              NAc  0   4 1   H H   H                                                                                ##STR826##                                         512                                                                              NH   0   4 1   H H   H                                                                                ##STR827##                                         513                                                                              NCH.sub.3                                                                          0   4 1   H H   H                                                                                ##STR828##                                         514                                                                              NCH.sub.2 Ph                                                                       0   4 1   H H   H                                                                                ##STR829##                                         515                                                                              NH   0   4 1   H H   H                                                                                ##STR830##                                         516                                                                              NCH.sub.2 Ph                                                                       1   3 1   H H   H                                                                                ##STR831##                                         517                                                                              NAc  1   3 1   H H   H                                                                                ##STR832##                                         518                                                                              NCH.sub.3                                                                          1   3 1   H H   H                                                                                ##STR833##                                         519                                                                              NCH.sub.2 Ph                                                                       1   3 1   H H   H                                                                                ##STR834##                                         520                                                                              NH   1   3 1   H H   H                                                                                ##STR835##                                         __________________________________________________________________________

                                      TABLE 30                                    __________________________________________________________________________     ##STR836##                                                                        ##STR837##                                                                          ##STR838##                                                                       ##STR839##                                                                       ##STR840##                                                                       ##STR841##                                                                       ##STR842##                                                                        ##STR843##                                                                       ##STR844##                                      __________________________________________________________________________    521 NCH.sub.2 Ph                                                                        0  2  2  H  OH  H                                                                                 ##STR845##                                      522 NCH.sub.2 Ph                                                                        0  2  2  H  OCH.sub.3                                                                         H                                                                                 ##STR846##                                      523 NCH.sub.2 Ph                                                                        0  3  2  H  OH  H                                                                                 ##STR847##                                      524 NCH.sub.2 Ph                                                                        0  3  2  H  OCH.sub.3                                                                         H                                                                                 ##STR848##                                      525 NCHO  0  2  2  H  H   H                                                                                 ##STR849##                                      526 NCHO  0  3  2  H  H   H                                                                                 ##STR850##                                      527 NCH.sub.2 Ph                                                                        0  2  2  H  H   H                                                                                 ##STR851##                                      528 NCH.sub.2 Ph                                                                        0  3  2  H  H   H                                                                                 ##STR852##                                      __________________________________________________________________________

                                      TABLE 31                                    __________________________________________________________________________     ##STR853##                                                                    ##STR854##                                                                       ##STR855##                                                                                     ##STR856##                                                                      ##STR857##                                                                      ##STR858##                                                                      ##STR859##                                                                      ##STR860##                                                                      ##STR861##                                                                      ##STR862##                                   __________________________________________________________________________    529                                                                               ##STR863##      2 2 2 H H H                                                                                ##STR864##                                   530                                                                               ##STR865##      2 2 2 H H H                                                                                ##STR866##                                   531                                                                               ##STR867##      2 2 2 H H H                                                                                ##STR868##                                   532                                                                               ##STR869##      2 2 2 H H H                                                                                ##STR870##                                   533                                                                               ##STR871##      2 2 2 H H H                                                                                ##STR872##                                   534                                                                               ##STR873##      2 2 2 H H H                                                                                ##STR874##                                   535                                                                               ##STR875##      2 2 2 H H H                                                                                ##STR876##                                   536                                                                               ##STR877##      2 2 2 H H H                                                                                ##STR878##                                   537                                                                               ##STR879##      2 2 2 H H H                                                                                ##STR880##                                   538                                                                               ##STR881##      2 2 2 H H H                                                                                ##STR882##                                   539                                                                               ##STR883##      2 2 2 H H H                                                                                ##STR884##                                   540                                                                               ##STR885##      2 2 2 H H H                                                                                ##STR886##                                   541                                                                               ##STR887##      2 2 2 H H H                                                                                ##STR888##                                   542                                                                               ##STR889##      2 2 2 H H H                                                                                ##STR890##                                   543                                                                               ##STR891##      2 2 2 H H H                                                                                ##STR892##                                   544                                                                               ##STR893##      2 2 2 H H H                                                                                ##STR894##                                   545                                                                               ##STR895##      2 2 2 H H H                                                                                ##STR896##                                   546                                                                               ##STR897##      2 2 2 H H H                                                                                ##STR898##                                   __________________________________________________________________________

                                      TABLE 32                                    __________________________________________________________________________     ##STR899##                                                                       ##STR900##                                                                                    ##STR901##                                                                      ##STR902##                                                                      ##STR903##                                                                      ##STR904##                                                                      ##STR905##                                                                      ##STR906##                                                                      ##STR907##                                    __________________________________________________________________________    547                                                                               ##STR908##     2 2 2 H H H                                                                                ##STR909##                                    548                                                                               ##STR910##     2 2 2 H H H                                                                                ##STR911##                                    549                                                                               ##STR912##     2 2 2 H H H                                                                                ##STR913##                                    550                                                                               ##STR914##     2 2 2 H H H                                                                                ##STR915##                                    551                                                                               ##STR916##     2 2 2 H H H                                                                                ##STR917##                                    552                                                                               ##STR918##     2 2 2 H H H                                                                                ##STR919##                                    553                                                                               ##STR920##     2 2 2 H H H                                                                                ##STR921##                                    554                                                                               ##STR922##     2 2 2 H H H                                                                                ##STR923##                                    555                                                                               ##STR924##     2 2 2 H H H                                                                                ##STR925##                                    556                                                                               ##STR926##     2 2 2 H H H                                                                                ##STR927##                                    557                                                                               ##STR928##     2 2 2 H H H                                                                                ##STR929##                                    558                                                                               ##STR930##     2 2 2 H H H                                                                                ##STR931##                                    559                                                                               ##STR932##     2 2 2 H H H                                                                                ##STR933##                                    560                                                                               ##STR934##     2 2 2 H H H                                                                                ##STR935##                                    561                                                                               ##STR936##     2 2 2 H H H                                                                                ##STR937##                                    562                                                                               ##STR938##     2 2 2 H H H                                                                                ##STR939##                                    563                                                                               ##STR940##     2 2 2 H H H                                                                                ##STR941##                                    564                                                                               ##STR942##     2 2 2 H H H                                                                                ##STR943##                                    565                                                                               ##STR944##     2 2 2 H H H                                                                                ##STR945##                                    566                                                                               ##STR946##     2 2 2 H H H                                                                                ##STR947##                                    __________________________________________________________________________

                                      TABLE 33                                    __________________________________________________________________________     ##STR948##                                                                       ##STR949##                                                                                    ##STR950##                                                                      ##STR951##                                                                      ##STR952##                                                                      ##STR953##                                                                      ##STR954##                                                                      ##STR955##                                                                      ##STR956##                                    __________________________________________________________________________    567                                                                               ##STR957##     2 2 2 H H H                                                                                ##STR958##                                    568                                                                               ##STR959##     2 2 2 H H H                                                                                ##STR960##                                    569                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR961##                                    570                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR962##                                    571                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR963##                                    572                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR964##                                    573                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR965##                                    574                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR966##                                    575                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR967##                                    576                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR968##                                    577                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR969##                                    578                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR970##                                    579                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR971##                                    580                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR972##                                    581                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR973##                                    582                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR974##                                    583                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR975##                                    584                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR976##                                    585                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR977##                                    586                                                                              NCH.sub.2 Ph    2 2 2 H H H                                                                                ##STR978##                                    __________________________________________________________________________

                                      TABLE 34                                    __________________________________________________________________________     ##STR979##                                                                       ##STR980##                                                                         ##STR981##                                                                      ##STR982##                                                                      ##STR983##                                                                      ##STR984##                                                                      ##STR985##                                                                        ##STR986##                                                                      ##STR987##                                             __________________________________________________________________________    587                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H   H                                                                                ##STR988##                                             588                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H   H                                                                                ##STR989##                                             589                                                                              NCH.sub.2 Ph                                                                       2 2 2 H OH  H                                                                                ##STR990##                                             590                                                                              NCH.sub. 2 Ph                                                                      2 2 2 H OCH.sub.3                                                                         H                                                                                ##STR991##                                             591                                                                              NCH.sub.2 Ph                                                                       2 2 2 H Cl  H                                                                                ##STR992##                                             592                                                                              NCH.sub.2 Ph                                                                       2 2 2 H Br  H                                                                                ##STR993##                                             593                                                                              NCH.sub.2 Ph                                                                       2 2 2 H CH.sub.3                                                                          H                                                                                ##STR994##                                             594                                                                              NCH.sub.2 Ph                                                                       1 3 2 H OH  H                                                                                ##STR995##                                             595                                                                              NCH.sub.2 Ph                                                                       1 3 2 H OCH.sub.3                                                                         H                                                                                ##STR996##                                             596                                                                              NCH.sub.2 Ph                                                                       0 3 2 H OH  H                                                                                ##STR997##                                             597                                                                              NCH.sub.2 Ph                                                                       0 3 2 H OCH.sub.3                                                                         H                                                                                ##STR998##                                             598                                                                              NCHO 2 1 2 H H   H                                                                                ##STR999##                                             599                                                                              NCHO 0 3 2 H H   H                                                                                ##STR1000##                                            600                                                                              NCHO 1 3 2 H H   H                                                                                ##STR1001##                                            601                                                                              NCHO 0 4 2 H H   H                                                                                ##STR1002##                                            602                                                                              NCHO 0 5 2 H H   H                                                                                ##STR1003##                                            603                                                                              NCH.sub.2 Ph                                                                       2 2 2 H H   H                                                                                ##STR1004##                                            604                                                                              NCH.sub.2 Ph                                                                       1 3 2 H H   H                                                                                ##STR1005##                                            605                                                                              NCH.sub.2 Ph                                                                       0 3 2 H H   H                                                                                ##STR1006##                                            __________________________________________________________________________

In the tables, Ac stands for acetyl group, and Ph stands for phenylgroup.

As salts of the compounds [I] and [VII] of this invention,physiologically acceptable acid addition salts are especiallypreferable. Examples of these salts include salts with inorganic acids(e.g. hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuricacid), and salts with organic acids (e.g. acetic acid, formic acid,propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid,citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonicacid, benzenesulfonic acid). And, in the case where the compounds [I]and [VII] of this invention have an acid group such as --COOH, they mayform salts with inorganic bases (e.g. an alkali metal or alkaline earthmetal such as sodium, potassium, calcium, magnesium etc., ammonia) ororganic bases (e.g. tri--C₁₋₃ alkylamine such as triethylamine, etc.).

In the following, the process of producing the compound [I] or its saltsof the present invention is described.

While the following description applies not only to the production ofthe compound [I] per se but also to the production of its salts, thesecompounds are simply referred to as the compound [I] inclusively in thedescription.

The compound [I] can be produced by, for example, reacting a compoundrepresented by the formula: ##STR1007## wherein each symbol has the samemeaning as defined above, or a salt thereof, with a compound representedby the formula: ##STR1008## wherein each symbol has the same meaning asdefined. above or a salt thereof.

As the leaving group shown by Y in the formula [II], use is made of, forexample, halogen atoms (e.g. chlorine, bromine, iodine, etc.), C₁₋₆alkylsulfonyloxy group (e.g. methanesulfonyloxy, ethanesulfonyloxy,etc.), C₆₋₁₀ arylsulfonyloxy (e.g. benzenesulfonyloxy,p-toluenesulfonyloxy, etc.), etc. among them, halogen atoms arepreferable, more specifically, chlorine, bromine, etc.

As salts of the compound [II] and [III], use is made of, for example,salts with inorganic acids (e.g. hydrochloric acid, phosphoric acid,hydrobromic acid, sulfuric acid) or those with organic acids (e.g.acetic acid, formic acid, propionic acid, fumaric acid, maleic acid,succinic acid, tartaric acid, citric acid, malic acid, oxalic acid,benzoic acid, methanesulfonic acid, benzenesulfonic acid). And, in thecase where the compounds [II] and [III] of this invention have an acidgroup such as --COOH, they may form salts with inorganic bases (e.g. analkali metal or alkaline earth metal such as sodium, potassium, calcium,magnesium, etc., ammonia) or organic bases (e.g. tri--C₁₋₃ alkylaminesuch as triethylamine, etc.).

The amount of the compound [III] or a salt thereof to be employed inthis reaction ranges, usually, from 1.0 to 50.0 mol., preferably 1.0 to10.0 mol., relative to one mol. of the compound [II] or a salt thereof.This reaction can be conducted at temperatures ranging from 0° C to 120°C. The reaction time ranges, usually, from 10 minutes to 48 hours,preferably from 2 to 16 hours.

While this reaction can be conducted in the absence of solvent, it canbe conducted, upon necessity, in a solvent. As the solvent, any one canbe employed unless it hampers the reaction, exemplified by loweralcohols such as methanol, ethanol, propanol, isopropanol, n-butanol,t-butanol, etc., ethers such as dioxane, ether, tetrahydrofuran, etc.,aromatic hydrocarbons such as toluene, benzene, xylene, etc., amidessuch as dimethylformamide, dimethylacetamide,hexamethylphosphonotriamide, etc., esters such as ethyl acetate, butylacetate, etc. The amount the solvent to be employed ranges, usually,from 0.5 to 100 ml, preferably from 5 to 20 ml, relative to 1 mmol. ofthe compound [II] or salt thereof.

This reaction can also be conducted in the presence of a base, whennecessary. Examples of the base to be employed include inorganic basessuch as sodium carbonate, potassium carbonate, lithium carbonate, sodiumhydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide,sodium hydride, etc. and organic bases such as pyridine,4-dimethylaminopyridine, triethylamine, etc. The amount of the baseto+be employed ranges, usually, from equimol. to excess amount,preferably from 1.0 to 5.0 mol. relative to one mol. of the compound[III] or a salt thereof.

It is also possible to promote this reaction by allowing an iodide (e.g.sodium iodide, potassium iodide, lithium iodide) to be present in thereaction system. The amount of the iodide to be employed ranges, usuallyfrom 1 to 5 mol., preferably 1.0 to 1.5 mol., relative to one mol. ofthe compound [II] or a salt thereof.

The compound [I], wherein R¹ stands for an optionally substitutedhydrocarbon group or an optionally substituted acyl group, or a saltthereof can be produced by, for example, reacting a compound [I],wherein R¹ stands for H (R═H), or a salt thereof, with a compoundrepresented by the formula

    R.sup.1 '--Y.sup.2                                         [VIII]

wherein R¹ ' stands for an optionally substituted hydrocarbon group oran optionally substituted acyl group, and Y² stands for a leaving group,or a salt thereof.

Examples of the salts of the compound [VIII] include those withinorganic acids (e.g. hydrochloric acid, phosphoric acid, hydrobromicacid, sulfuric acid) or organic acids (e.g. acetic acid, formic acid,propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid,citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonicacid, benzenesulfonic acid). Further, in the case where the compound[VIII] of this invention has an acid group such as --COOH, the compound[VIII] may be in the form of salt with an inorganic base (e.g. an alkalimetal or alkaline earth metal such as sodium, potassium, calcium,magnesium, etc., ammonia) or an organic base (e.g. tri--C₁₋₃ alkylaminesuch as triethylamine, etc.).

As the leaving group shown by Y², use is made of, for example, a halogenatom (e.g. chlorine, bromine, iodine), C₁₋₆ alkylsulfonyloxy group (e.g.methanesulfonyloxy, ethanesulfonyloxy), C₆₋₁₀ arylsulfonyloxy group(e.g. benzenesulfonyloxy, p-toluenesulfonyloxy), etc. Especially,halogen atoms are preferable.

As the optionally substituted hydrocarbon groups shown by R¹ ', use ismade of, for example, the optionally substituted hydrocarbon groupsshown by R¹ as described in the foregoing. As the optionally substitutedacyl groups shown by R¹ ', use is made of, for example, the optionallysubstituted acyl groups shown by R¹ as described in the foregoing.

Further, the compound [I] (R═H) or a salt thereof can be produced alsoby subjecting a compound [I], wherein R¹ stands for an optionallysubstituted acyl group, or a salt thereof to hydrolysis with an acid ora base, in the same manner as in conventional hydrolysis.

The starting compound [II] or a salt thereof can be produced by reactinga compound represented by the formula: ##STR1009## wherein each symbolhas the same meaning as defined above, or a salt thereof, with acompound represented by the formula: ##STR1010## wherein Y¹ stands for aleaving group, and other symbols are of the same meanings as definedabove.

As salts of the compound [IX], use is made of, for example, salts withan inorganic acid (e.g. hydrochloric acid, phosphoric acid, hydrobromicacid, sulfuric acid) or an organic acid (e.g. acetic acid, formic acid,propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid,citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonicacid, benzenesulfonic acid). Further, in the case where the compound[IX] of this invention has an acid group such as --COOH, the compound[IX] may be in the form of a salt with an inorganic base (e.g. an alkalimetal or an alkaline earth metal such as sodium, potassium, calcium,magnesium, etc., ammonia) or an organic base (e.g. tri--C₁₋₃ alkylaminesuch as triethylamine, etc.).

As the leaving group shown by Y¹, use is made of, for example, halogenatoms (e.g. chlorine, bromine, iodine), C₁₋₆ alkylsulfonyloxy group(e.g. methanesulfonyloxy, ethanesulfonyloxy), C₆₋₁₀ arylsulfonyloxygroup (e.g. benzenesulfonyloxy, p-toluenesulfonyloxy), etc. Especially,halogen atoms are preferable.

The compound [IX] or salts thereof can be produced in accordance with aper se known method or a method analogous thereto, for example, asdescribed in J. Org. Chem. 34, 2235 (1969), J. Org Chem. 54, 5574(1989), Tetrahedron Lett. 35, 3023 (1977), and Bull. Chem. Soc. Jpn. 56,2300 (1983).

The compound [X] can be produced by a per se known method or a methodanalogous thereto.

The reaction of the compound [IX] or a salt thereof with the compound[X] can be conducted by using, for example, usually about 1 to 20 mol.,preferably about 1 to 5 mol., of the compound [X] or a salt thereofrelative to 1 mol. of the compound [IX], in the presence of, forexample, a Lewis acid.

This reaction can be conducted without using a solvent or, uponnecessity, in a solvent. As the solvent, any one which is conventionallyusable in chemical reactions, unless it hampers the reaction, can beemployed, as exemplified by organic solvents including hydrocarbons(e.g. pentane, hexane, benzene, toluene, nitrobenzene, etc.),halogenated hydrocarbons (e.g. dichloromethane, chloroform,1,2-dichloroethane, carbon tetrachloride, etc.), ethers (e.g. ethylether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitro alkanes(e.g. nitromethane, propionitrile, etc.), and carbon disulfide.Especially, dichloromethane, 1,2-dichloroethane, nitrobenzene and carbondisulfide are preferable. The amount of the solvent ranges usually from0.5 to 100 ml, preferably from 5 to 20 ml, relative to 1 mmol. of thecompound [IX] or a salt thereof.

The reaction temperature ranges usually from from about -30° C. to about150° C., preferably from about 20° C. to about 100° C. The reaction timeranges usually from 0.5 to 72 hours, preferably from 1 to 16 hours.

And, as the Lewis acid to be employed in this reaction, use is made of,for example, aluminum chloride, zinc chloride, titanium chloride,tin(IV) chloride, boron trifluoride, iron(II) chloride, iron(III)chloride, antimony pentachloride (V), bismuth chloride (III), silverchloride (II), hydrogen fluoride, sulfuric acid, polyphosphoric acid,etc. Among them, aluminum chloride and the like are preferable. Theamount of the Lewis acid to be employed ranges usually from 1 to 10mol., preferably from 2 to 10 mol., relative to 1 mol. of the compound[IX] or a salt thereof.

In the above reaction, the position where the group of the compound [X]##STR1011## is introduced into the compound [IX] or a salt thereof maybe any of the positions on ring A on which the substitution can takeplace. For example, in the case where the skeleton of the compound [IX]or a salt thereof is 1,2,3,4-tetrahydroquinoline (provided that the ringA is unsubstituted), the group of the compound [X] is introducedprincipally into 6-position, while such compounds as having the groupintroduced at any other positions (5-position, 7-position, 8-position)can be produced and separated as well.

The compound [II] or salts thereof obtained thus above can be isolatedand refined by a conventional means such as concentration, pH change,phasic transfer, solvent extraction, fractional distillation,distillation, crystallization, recrystallization and chromatography,while they may be fed to the subsequent process as the material in thestate of reaction mixture without isolation.

The starting compound [III] or salts thereof can be produced by a per seknown method or a method analogous thereto.

The compound [VIII] or salts thereof can be produced by a Der se knownmethod or a method analogous thereto.

And, among the compounds [I], those where n is 2, i.e. the compound ofthe formula: ##STR1012## wherein each symbol is of the same meaning asdefined above, or a salt thereof, can be produced also by reacting acompound of the formula: ##STR1013## wherein each symbol is of the samemeaning as defined above, or a salt thereof, with a compound representedby the formula:

    R.sup.6 --CHO [V]

wherein R⁶ is of the same meaning as defined above and a compoundrepresented by the formula: ##STR1014## wherein each symbol is of thesame meaning as defined above, or a salt thereof.

As salts of the compound [IV], use is made of, for example, those withinorganic acids (e.g. hydrochloric acid, phosphoric acid, hydrobromicacid, sulfuric acid) or with organic acids (e.g. acetic acid, formicacid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaricacid, citric acid, malic acid, oxalic acid, benzoic acid,methanesulfonic acid, benzenesulfonic acid). Further, in the case wherethe compound [IV] of this invention has an acid group such as --COOH,compound [IV] may be in the form of a salt with an inorganic base (e.g.alkali metal or alkaline earth metal such as sodium, potassium, calcium,magnesium, etc., ammonia) or with an organic base (e.g. tri-C₁₋₃alkylamine such as triethylamine, etc.).

This reaction can be conducted in substantially the same manner as theMannich reaction described in Organic Reaction, Vol. 1, p 303 to 341.More specifically, this reaction is conducted by reacting, for example,compound [V] and the compound [III] or a salt thereof, with the compound[IV] or a salt thereof in a ratio of usually 0.9 to 10, preferably 1.0to 3.0, equivalents of the former relative to 1 equivalent of thelatter. Wile this reaction can be carried out usually at temperaturesranging from room temperature to under heating (10 to 150° C.), it isconducted preferably at temperatures ranging from 80 to 120° C. Theaction time ranges usually from 1 to 48 hours, preferably from 2 to 24hours. This reaction can usually be conducted in the absence or presenceof solvent. As the solvent, any one to be used in general for Mannichreaction can be employed, unless it hampers this reaction. For example,alcohols such as ethanol are often employed. The amount of the solventranges usually from 0.5 to 200 ml, preferably from 5 to 40 ml, relativeto 1 mmol. of the compound [IV] or a salt thereof. Further, thisreaction can be conducted, when desired, in the presence of an inorganicacid such as hydrochloric acid. The acid is used in a catalytic amountrelative to the compound [.IV] or a salt thereof (0.001 to 0.05equivalent relative to 1 equivalent of the compound [IV] or a saltthereof). In the case where the compound [III] or [IV] to be employedfor the reaction is not in the form of salt, however, it is preferableto use the acid in an excess amount sufficient for allowing thesecompounds to form salts.

The compound [IV] or salts thereof and the compound [V] can be producedby a per se known method or a method analogous thereto.

Further, the compound [I] or a salt thereof can be produced also byfirst hydrolizing the ester moiety (COOR²) of, for example, a compoundrepresented by the formula: ##STR1015## wherein each symbol is of thesame meaning as defined above or a salt thereof, which can be obtainedby the method described above, then by subjecting the reaction mixtureto decarboxylation. The hydrolysis and decarboxylation can be conductedin the same manner as per se known methods.

And, the compound [I] or a salt thereof can be produced also bysubjecting, for example, a compound, wherein R¹ is carboxylic acid acyl,or a salt thereof to reduction in a conventional manner. In thisreaction, it is preferable that, upon necessity, the functional group(e.g. ketone) of the compound [I] or a salt thereof (R¹ =carboxylic acidacyl group) is first protected, in the form of acetal with, for example,ethylene glycol or any other alcohol (e.g. methanol, ethanol, etc.),then the thus protected compound is subjected to reduction, and then thereaction mixture is subjected to deprotection with an acid or base or byheating.

And, in each of the above-mentioned reactions, in the case where thestarting compound has, as substituents, amino group, carboxyl group,hydroxyl group, etc., these groups may be protected with such protectinggroups as generally used in peptide chemistry, and the object compoundcan be obtained by, upon necessity, removing these protecting groupsafter the reaction.

As the protecting groups of amino group, use is made of, for example,formyl, optionally substituted C₁₋₆ alkyl-carbonyl groups (e.g. acetyl,ethylcarbonyl, etc.), benzoyl, C₁₋₆ alkyloxy-carbonyl (e.g.methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl (e.g.phenoxycarbonyl, etc.), C₇₋₁₅ aralkyloxy-carbonyl (e.g.benzyloxycarbonyl, fluorenyloxycarbonyl, etc.), trityl, phthaloyl, etc.As substituents on these groups, use is made of halogen atoms (e.g.fluorine, chlorine, bromine, iodine, etc.), C₁₋₆ alkyl-carbonyl (e.g.methyl-carbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group, amongothers, and the number of these substituents ranges from 1 to 3. As theprotecting group of carboxyl group, use is made of, for example, anoptionally substituted C₁₋₆ alkyl (e.g. methyl, ethyl, n-propyl,i-propyl, n-butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc. Assubstituents on these groups, use is made of halogen atoms (e.g.fluorine, chlorine, bromine, iodine, etc.), formyl, C₁₋₆ alkyl carbonyl(e.g. methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro, etc.,and the number of these substituents ranges from 1 to 3. As the groupprotecting hydroxyl group, use is made of, for example, an optionallysubstituted C₁₋₆ alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl,tert-butyl, etc.), phenyl, C₇₋₁₀ aralkyl (e.g. benzyl, etc.), formyl,C₁₋₆ alkyl carbonyl (e.g. acetyl, ethylcarbonyl, etc.),phenyloxycarbonyl, C₇₋₁₀ aralkyl-carbonyl (e.g. benzyloxycarbonyl,etc.), pyranyl, furanyl, silyl, etc. As substituents on these groups,use is made of halogen atom (e.g. fluorine, chlorine, bromine, iodine,etc.), C₁₋₆ alkyl, phenyl, C₇₋₁₀ aralkyl, nitro group, etc., and thenumber of these substituents ranges from 1 to 4.

And, as the means of removing these protecting groups, use is made of.per se known means or those analogous thereto, as exemplified by thosewhich comprise processing with an acid, a base, reduction, UV-ray,hydrazine, phenyl hydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate, etc.

Further, the compound [VII] of this invention or salts thereof can beproduced by substantially the same method as described above for theproduction of the compound [I] or salts thereof, using a compoundwherein the group ##STR1016## in, for example, the starting compound[II], [IV], [IX] or a salt thereof, is a group ##STR1017##

The compound [I] or salts thereof and the compound [VII] or saltsthereof thus obtained above can be isolated and refined by conventionalseparating means such as recrystallization, distillation,chromatography, etc. In the case where the compound [I] and the compound[VII] thus obtained above are in the free form, they can be converted tosalts by per se conventional means or those analogous thereto.Conversely, when the compound [I] or [VII] is obtained in the form ofsalt, it can be converted to the free compound or any other salt by perse conventional means or those analogous thereto.

The compound [I] or salts thereof and the compound [VII] or saltsthereof include their stereoisomers due to the presence of asymmetriccarbon atoms. These isomers can be resolved into corresponding opticallyactive compounds by means of a conventional optical resolution.

The compound [I] or salts thereof and the compound [VII] or saltsthereof of the present invention act on the central nervous system ofmammals, have strong cholinesterase inhibitory activity, and exhibitexcellent antiamnestic effects on various amnesia-inducing actions inman and animals (e.g. mice, etc.). Further, the compound [I] or saltsthereof and the compound [VII] or salts thereof of the present inventionhave monoamine (e.g. norepinephrine, serotonin, etc.) reuptakeinhibitory activity, and exhibit excellent antidepressant activity, etc.in man and animals (e.g. mice, etc.).

The compound [I] or salts thereof and the compound [VII] or saltsthereof of the present invention are remarkably excellent in separationof effects on central nervous system from those on peripheral nervoussystem, as compared with physostigmine and, at the antiamnestic andantidepressant dose level, do not cause peripheral nervous systemeffects such as spasm, salivation, diarrhea, etc. or, if they do, onlyslightly. Moreover, they are characterized by a long duration of effectsand low toxicity, ensuring a remarkably high efficacy when administeredorally. The acute toxicity of the compound [I] or salts thereof and thecompound [VII] or salts thereof of the present invention is not lessthan 100 mg/kg. Therefore, the compounds of this invention are useful asa safely administrable agent for improving the cerebral function ofmammalian animals including human beings.

Diseases on which the compounds of this invention are effective includesenile dementia, Alzheimer's diseases, Huntington's chorea, hyperkinesiaand mania. The compounds of this invention can be used for theprophylaxis or therapy of these diseases. Further, the compounds of thisinvention can be also used for the prophylaxis or therapy of depression,hypobulia, affective disorders, lack of spontaneity, etc. which aresymptoms related to the above-mentioned diseases.

The compounds of this invention are usually formulated withpharmaceutically acceptable carriers or excipients, which can beadministered orally or non-orally to man and other mammalian animals.Such pharmaceutical preparations may be those for oral administration(e.g. powders, tablets, granules and capsules) and for non-oraladministration (e.g. suppositories, injections). These pharmaceuticalcompositions can be prepared by Der se known methods. While the dosagedepends on the type and symptom of diseases to be treated, in the caseof oral administration to general adult humans (60 kg body weight), itranges from about 0.01 mg to about 50 mg, preferably from 0.1 to 30 mg,more preferably from 0.5 to 10 mg per day.

By the following working examples, reference examples, formulationexamples and experimental examples, the present invention will beillustrated in more concrete manner, but they should by no means beconstrued as defining the metes and bounds of this invention.

In the experimental examples and reference examples, elution in theprocedure of column chromatography was carried out under observation bymeans of TLC (Thin Layer Chromatography) unless otherwise specified. Inthe TLC observation, 60F₂₅₄ manufactured by Merck was employed as theTLC plate, the solvent employed as elution solvent for the columnchromatography was employed as the developer, and a UV detector wasemployed for detection. As an adjunctive detection procedure, the spoton the TLC plate was sprayed with 48% HBr, heated to hydrolize, sprayedwith a ninhydrin reagent and heated again, then the change to ared--reddish purple was regarded as positive reaction. The fractionscontaining the object compound were pooled. Unless otherwise specified,Merck Kieselgel 60 (70 to 230 mesh) was employed as the silica gel forthe column.

Incidentally, the term "ambient temperature" or "room temperature"generally means usually temperatures ranging from about 5° C. to 40° C.,and the term "atmospheric pressure" means the neighborhood of oneatmospheric pressure.

And, unless otherwise specified, % denotes percentage by weight.

REFERENCE EXAMPLE 14-Chloro-1-(3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-butanone##STR1018##

In 30 ml of dichloromethane, was dissolved 3.79 g of3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine. To the solution were added3.38 g of 4-chlorobutyryl chloride and 4.00 g of aluminum chloride. Themixture was stirred for 2 hours at room temperature (about 20° C.). Thereaction mixture was poured into 50 ml of ice-water. The organic layerwas separated, which was washed successively with 50 ml of 0.5N aqueoussolution of sodium hydroxide and 50 ml of pure water, then dried overanhydrous sodium sulfate. The solvent was distilled off to leave 5.40 gof an oily residue. The residue was purified by means of a silica gelcolumn chromatography (developing solvent, ethyl acetate-dichloromethane1:1 (V/V)) to afford 2.92 g of the title compound as colorless crystals,m.p.103°-106° C.

Elemental Analysis for C₁₆ H₂₀ ClNO₂ :

Calcd.: C, 65.41; H, 6.86; N, 4.77

Found : C, 65.33; H, 6.91; N, 4.69

REFERENCE EXAMPLE 2

By conducting substantially the same procedure as in Reference Example1, compounds shown in Table 35 were obtained.

                  TABLE 35                                                        ______________________________________                                         ##STR1019##                                                                                                  Elemental Analysis                            Compound      m.p.     Molecular                                                                              Calcd. (Found)                                No.     n     (°C.)                                                                           Formula  C     H    N                                  ______________________________________                                        1       1     128-130  C.sub.14 H.sub.16 ClNO.sub.2                                                           63.28 6.07 5.27                                                               (63.09                                                                              6.12 5.26)                              2       2     123-124  C.sub.15 H.sub.18 ClNO.sub.2                                                           64.40 6.48 5.01                                                               (64.33                                                                              6.47 4.94)                              ______________________________________                                    

REFERENCE EXAMPLE 37-Acetyl-3-(phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepine##STR1020##

To 7.36 g of 2,3,4,5-tetrahydro-1H-3-benzazepine and 10.37 g ofpotassium carbonate, was added 75 ml of ethanol. To the mixture, wasadded dropwise 8.38 g of benzyl bromide under ice-cooling in the courseof 10 minutes, followed by stirring for 2 hours at 25° C., then thesolvent was distilled off. To the residue were added 100 ml of purewater and 100 ml of dichloromethane, then the organic layer wasseparated and dried over sodium sulfate, followed by distilling off thesolvent to leave a crystalline residue.

The residue was dissolved in 20 ml of methanol, to which was added 19 mlof 4N methanolic hydrochloric acid. Methanol was then distilled off, andthe residue was suspended in 100 ml of ethyl acetate. Resulting crystalswere collected by filtration, then the crystals were washed with 30 mlof ethyl acetate. The crystals were dried under reduced pressure to give11.94 g of 3-(phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride.

10.95 g of the above-mentioned compound was dissolved in 80 ml of1,2-dichloroethane, to which were added 10.67 g of aluminum chloride and4.71 g of acetyl chloride, then the mixture was stirred for 30 minutesunder reflux. The reaction mixture was poured into 150 ml of ice-water,then pH of the aqueous layer was adjusted to 10, followed by addition of150 ml of dichloromethane. The organic layer was separated and driedover sodium sulfate. The solvent was then distilled off to leave 13.0 gof an oily residue. The residue was purified by means of a silica gelcolumn chromatography (developing solvent, ethyl acetate-dichloromethane1:2) to afford 10.44 g of the title compound as colorless crystals,m.p.89°-91° C.

Elemental Analysis for C₁₉ H₂₁ NO:

Calcd.: C, 81.68; H, 7.58; N, 5.01

Found : C, 81.49; H, 7.61; N, 4.86

REFERENCE EXAMPLE 4 Ethylβ-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-β-oxopropionate##STR1021## (1) To a solution of 18.9 g of1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepine in 20 ml of carbondisulfide were first added 30.8 g of aluminum chloride then 7.8 ml ofacetyl chloride gradually at room temperature. The mixture was heatedfor 16 hours under reflux. The reaction mixture was poured into icewater, which was subjected to extraction with dichloromethane. Theextract solution was dried over anhydrous sodium sulfate, then thesolvent was distilled off. The residue was purified by means ofchromatography (developing solvent; dichloromethane ethylacetate=5:1(V/V)) to give 13.5 g of pale yellow crystals.Recrystallization from diethyl ether-hexane affords 12.4 g of1,8-diacetyl-2,3,4,5-tetrahydro-1H-1-benzazepine as colorless crystals,m.p.105°-108° C.

Elemental Analysis for C₁₄ H₁₇ NO₂ :

Calcd.: C, 72.70; H, 7.41; N, 6.06

Found : C, 72.82; H, 7.36; N, 6.00

(2) To a refluxed solution of 3.83 g of diethyl carbonate and 1.04 g ofsodium hydride (oil free) in 50 ml of tetrahydrofuran was addeddropwise, under nitrogen atmosphere, a solution of 5 g of1,8-diacetyl-2,3,4,5-tetrahydro-1H-1-benzazepine in 50 ml oftetrahydrofuran. The mixture was heated for 3 hours under reflux, thenthe reaction mixture was poured into ice-water, which was subjected toextraction with dichloromethane. The extract solution was dried overanhydrous sodium sulfate, then the solvent was distilled off. Theresidue was purified by means of chromatography (developing solvent;dichloromethane-ethyl acetate=5:1(V/V)) to afford 3.5 g of the titlecompound as a colorless oily product.

Elemental Analysis for C₁₇ H₂₁ NO₄ :

Calcd.: C, 67.31; H, 6.98; N, 4.62

Found : C, 67.14; H, 6.83; N, 4.63

REFERENCE EXAMPLE 5

By substantially the same procedure as in Reference Example 1, compoundslisted in Table 36 were obtained.

                                      TABLE 36                                    __________________________________________________________________________     ##STR1022##                                                                                                  Elemental Analysis                            Compound            m.p. Molecular                                                                            Calcd. (Found)                                No.   X     k m n Y (°C.)                                                                       Formula                                                                              C   H  N                                      __________________________________________________________________________    1     NAc   0 4 1 Cl                                                                              112-115                                                                            C.sub.14 H.sub.16 ClNO.sub.2                                                         63.28                                                                             6.07                                                                             5.27                                                                   (63.11                                                                            6.14                                                                             5.33)                                  2     NAc   0 4 2 Cl                                                                              123-124                                                                            C.sub.15 H.sub.18 ClNO.sub.2                                                         64.40                                                                             6.49                                                                             5.01                                                                   (64.35                                                                            6.56                                                                             4.91)                                  3     NCO.sub.2 Et                                                                        0 4 2 Cl                                                                              oil  C.sub.16 H.sub.20 ClNO.sub.3                                                         62.03                                                                             6.51                                                                             4.52                                                                   (62.19                                                                            6.40                                                                             4.50)                                  4     NCH.sub.2 Ph                                                                        2 2 1 Cl                                                                              111-113                                                                            C.sub.19 H.sub.20 ClNO                                                               72.72                                                                             6.42                                                                             4.46                                                                   (72.50                                                                            6.45                                                                             4.44)                                  5     NCH.sub.2 Ph                                                                        2 2 2 Cl                                                                              176-178                                                                            C.sub.20 H.sub.22 ClNO.                                                              65.94                                                                             6.36                                                                             3.84                                                            HCl    (65.67                                                                            6.52                                                                             3.77)                                  6     NCH.sub.2 Ph                                                                        2 2 5 Br                                                                              oil  C.sub.23 H.sub.28 BrNO                                                               66.67                                                                             6.81                                                                             3.38                                                                   (66.57                                                                            6.83                                                                             3.37)                                  *7    NCHO  2 0 2 Cl                                                                              134-136                                                                            C.sub.12 H.sub.12 ClNO.sub.2                                                         60.64                                                                             5.09                                                                             5.89                                                                   (60.45                                                                            4.88                                                                             5.67)                                  8     NCHO  1 3 2 Cl                                                                              94-96                                                                              C.sub.14 H.sub.16 ClNO.sub.2                                                         63.28                                                                             6.07                                                                             5.27                                                                   (63.37                                                                            6.14                                                                             5.23)                                  9     NCHO  2 2 2 Cl                                                                              121-123                                                                            C.sub.14 H.sub.16 ClNO.sub.2                                                         63.28                                                                             6.07                                                                             5.27                                                                   (63.17                                                                            6.02                                                                             5.31)                                  10    NAc   2 2 4 Cl                                                                              95-98                                                                              C.sub.17 H.sub.22 ClNO.sub.2                                                         66.33                                                                             7.20                                                                             4.55                                                                   (66.35                                                                            7.11                                                                             4.60)                                  11    NCO.sub.2 CH.sub.3                                                                  2 2 2 Cl                                                                              117-120                                                                            C.sub.15 H.sub.18 ClNO.sub.3                                                         60.92                                                                             6.13                                                                             4.74                                                                   (60.97                                                                            6.10                                                                             4.77)                                  *12   NCHO  3 0 2 Cl                                                                              103-105                                                                            C.sub.13 H.sub.14 ClNO.sub.2                                                         62.03                                                                             5.61                                                                             5.56                                                                   (62.15                                                                            5.59                                                                             5.70)                                  13    NCHO  0 3 2 Cl                                                                              oil  C.sub.13 H.sub.14 ClNO.sub.2                                                         62.03                                                                             5.61                                                                             5.56                                                                   (62.20                                                                            5.60                                                                             5.51)                                  14    NCHO  0 5 2 Cl                                                                              118-120                                                                            C.sub.15 H.sub.18 ClNO.sub.2                                                         64.40                                                                             6.48                                                                             5.01                                                                   (64.48                                                                            6.43                                                                             5.14)                                  *15   NAc   3 0 2 Cl                                                                              75-77                                                                              C.sub.14 H.sub.16 ClNO.sub.2                                                         63.28                                                                             6.07                                                                             5.27                                                                   (63.20                                                                            6.04                                                                             5.26)                                  16    NAc   0 5 2 Cl                                                                              oil  C.sub.16 H.sub.20 ClNO.sub.2                                                         65.41                                                                             6.86                                                                             4.77                                                                   (65.48                                                                            6.82                                                                             4.68)                                  __________________________________________________________________________     ##STR1023##                                                              

REFERENCE EXAMPLE 61-(3-Methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)2-propen-1-onehydrochloride ##STR1024##

In 30 ml of 1,2-dichloroethane, was dissolved 1.28 g of3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. To thesolution were added, at room temperature, 2.1 g of aluminum chloride and0.66 ml of 3-chloropropionyl chloride, then the mixture was stirred for2 hours. The reaction mixture was poured into 50 ml of ice-water, thenthe pH of the aqueous solution was adjusted to not lower than 9 with a40% aqueous solution of sodium hdyroxide, followed by extraction with 50ml of dichloromethane. The organic layer was washed with 50 ml of purewater, which was then dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure to give an oily residue, whichwas crystallized from dichloromethane-ether to afford 0.83 g of thetitle compound as pale yellow crystals, m.p.120°-123° C.

Elemental Analysis for C₁₄ H₁₇ NO.HCl.H₂ O:

Calcd.: C, 62.33; H, 7.47; N, 5.19

Found : C, 62.53; H, 7.65; N, 5.13

REFERENCE EXAMPLE 7

By substantially the same procedure as in Reference Example 1, thecompounds shown in Table 37 were obtained.

                                      TABLE 37                                    __________________________________________________________________________     ##STR1025##                                                                                               Elemental Analysis                               Compound          m. p.                                                                              Molecular                                                                           Calcd. (Found)                                   No.   X    k m R.sup.2                                                                          (°C.)                                                                       Formula                                                                             C   H  N                                         __________________________________________________________________________    1     NCHO 2 2 Ph 140-142                                                                            C.sub.19 H.sub.19 NO.sub.2                                                          .sup. 77.79                                                                       6.53                                                                             4.77.sup.                                                              (77.51                                                                            6.43                                                                             4.89)                                     2     NCH.sub.2 Ph                                                                       2 2 Ph oil  C.sub.25 H.sub.25 NO                                                                .sup. 84.47                                                                       7.09                                                                             4.50.sup.                                                              (84.61                                                                            7.01                                                                             4.50)                                     __________________________________________________________________________

REFERENCE EXAMPLE 84-Bromo-1-(3-formyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-phenyl-1-butanone##STR1026##

In 50 ml of dimethylformamide was dissolved 2.93 g of the compound No.1obtained in Reference Example 7, to which was added 0.29 g of 60% sodiumhydride. The mixture was stirred for 30 minutes at room temperature, towhich was added 4.33 ml of 1,2-dibromoethane, then the mixture wasstirred for further 5 hours. The reaction mixture was poured into 150 mlof pure water, which was subjected to extraction with 150 ml of ethylacetate. The organic layer was washed twice with 150 ml each portion ofa saturated aqueous saline solution, which was dried over sodiumsulfate, followed by distilling off the solvent under reduced pressureto leave an oily residue. The oily residue was subjected to a silica gel(150 g) column chromatography, eluting with dichloromethane-ethylacetate (4:1), to afford 1.05 g of the title compound as a colorlessoily product.

Elemental Analysis for C₂₁ H₂₂ BrNO₂ :

Calcd.: C, 63.01; H, 5.54; N, 3.50

Found : C, 63.07; H, 5.62; N, 3.53

REFERENCE EXAMPLE 9

Using the compound obtained in Reference Example 7, substantially thesame procedure as in Reference Example 8 was followed to give thecompound shown in Table 38.

                                      TABLE 38                                    __________________________________________________________________________     ##STR1027##                                                                                                 Elemental Analysis                             Compound             m. p.                                                                            Molecular                                                                            Calcd. (Found)                                 No.   X    k m n R.sup.2                                                                         Y (°C.)                                                                     Formula                                                                              C   H  N                                       __________________________________________________________________________    1     NCH.sub.2 Ph                                                                       2 2 3 Ph                                                                              Br                                                                              oil                                                                              C.sub.27 H.sub.28 BrNO                                                               .sup. 70.13                                                                       6.10                                                                             3.03.sup.                                                              (70.02                                                                            6.13                                                                             3.02)                                   __________________________________________________________________________

WORKING EXAMPLE 1 1- (3-Acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4-(piperidin-1-yl)-1-butanone ##STR1028##

To a solution of 2.64 g of the compound obtained in Reference Example 1in 50 ml of toluene, were added 1.50 g of piperidine and 20 mg of KI.The mixture was stirred for 12 hours under reflux. The reaction mixturewas cooled, to which was then added 50 ml of pure water. The organiclayer was separated, from which the solvent was distilled off to leavean oily residue. The residue was purified by means of aluminachromatography (developing solvent; ethyl acetate) to afford 2.15 g ofthe title compound as colorless powder.

Elemental Analysis for C₂₁ H₃₀ N2O₂ :

Calcd.: C, 73.65; H, 8.83; N, 8.18

Found: C, 73.60; H, 8.74; N, 8.09

WORKING EXAMPLE 21-[3-(Phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-4-(piperidin-1-yl)-1-butanonedihydrochloride ##STR1029##

To 2.10 g of the compound obtained in Working Example 1 was added 21 mlof conc. hydrochloric acid, and the mixture was heated for 16 hoursunder reflux. Excess volume of the conc. hydrochloric acid was distilledoff under reduced pressure. To the residue was added 50 ml of water, andthe mixture was washed with 50 ml of dichloromethane. The aqueous layerwas made basic with an aqueous solution of sodium hydroxide, which wassubjected to extraction with dichloromethane. The extract solution wasdried over anhydrous sodium sulfate, then the solvent was distilled offto leave 1.80 g of an oily substance.

To a suspension of 1.80 g of the above-mentioned oily substance and 1.30g of potassium carbonate in 20 ml of ethanol was added dropwise asolution of 0.97 g of benzyl bromide in 5 ml of ethanol. The mixture wasstirred for 4 hours at room temperature. The solvent was distilled offunder reduced pressure. To the residue was added 30 ml of water, and themixture was subjected to extraction with dichloromethane. The extractsolution was dried over anhydrous sodium sulfate, followed by distillingoff the solvent to give 1.37 g of the free form of the title compound ascolorless powder, m.p.90°-92° C. 1.0 g of the thus obtained freecompound was dissolved in methanol, to which was added 1.5 ml of4N-methanolic hydrochloride. The solvent was distilled off under reducedpressure to leave a solid substance, which was recrystallized frommethanol-ethyl acetate to afford 0.93 g of the title compound ascolorless crystals, m.p.210°-215° C. (decomp.)

Elemental Analysis for C₂₆ H₃₄ N₂ O.2HCl:

Calcd.: C, 67.38; H, 7.83; N, 6.04

Found : C, 67.12; H, 7.81; N, 6.00

WORKING EXAMPLE 3

Using the compound obtained in Reference Example 2, the procedure ofWorking Example 1 was followed to give compounds shown in Table 39.

                                      TABLE 39                                    __________________________________________________________________________     ##STR1030##                                                                   ##STR1031##                                                                         ##STR1032##                                                                     ##STR1033##                                                                              ##STR1034##                                                                         ##STR1035##                                                                          ##STR1036##                                  __________________________________________________________________________    1     2                                                                                ##STR1037##                                                                             113-115                                                                              ##STR1038##                                                                          ##STR1039##                                                                       ##STR1040##                                                                      ##STR1041##                           2     2                                                                                ##STR1042##                                                                             181-182                                                                              ##STR1043##                                                                          ##STR1044##                                                                       ##STR1045##                                                                      ##STR1046##                           3     2                                                                                ##STR1047##                                                                              99-103                                                                              ##STR1048##                                                                          ##STR1049##                                                                       ##STR1050##                                                                      ##STR1051##                           4     2                                                                                ##STR1052##                                                                             170-175                                                                              ##STR1053##                                                                          ##STR1054##                                                                       ##STR1055##                                                                      ##STR1056##                           5     2                                                                                ##STR1057##                                                                              ##STR1058##                                                                         ##STR1059##                                                                          ##STR1060##                                                                       ##STR1061##                                                                      ##STR1062##                           __________________________________________________________________________

WORKING EXAMPLE 4

Using the compound obtained in Working Example 3, the procedure ofWorking Example 2 was followed to give the compound shown in Table 40.

                                      TABLE 40                                    __________________________________________________________________________     ##STR1063##                                                                   ##STR1064##                                                                         ##STR1065##                                                                     ##STR1066##                                                                           ##STR1067##                                                                         ##STR1068##                                                                          ##STR1069##                                     __________________________________________________________________________    1     2                                                                                ##STR1070##                                                                          163-165                                                                              ##STR1071##                                                                          ##STR1072##                                                                       ##STR1073##                                                                      ##STR1074##                              __________________________________________________________________________

WORKING EXAMPLE 51-[3-(Phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-3-(piperidin-1-yl)-1-propanonedihydrochloride ##STR1075##

To a solution of 1.40 g of the compound obtained in Reference Example 3,1.22 g of piperidine hydrochloride, 1.5 g of paraformaldehyde in 50 mlof ethanol was added 0.7 ml of conc. hydrochloride, and the mixture wasstirred for 24 hours under reflux. The solvent was distilled off. To theresidue were added 50 ml of ethyl acetate and 50 ml of pure water. Theaqueous layer was separated, whose pH was adjusted to not lower than 10,followed by extraction with 50 ml of ethyl acetate. The extract solutionwas dried over anhydrous sodium sulfate, from which the solvent wasdistilled off to leave 2.15 g of an oily residue.

The residue was purified by means of alumina chromatography (developingsolvent; dichloromethane-ethyl acetate=9:1) to give 1.4 g of an oilysubstance. The oily substance was dissolved in 15 ml of methanol, towhich was added 2.0 ml of 4N methanolic hydrochloric acid. The solventwas distilled off, and the crystalline residue was recrystallized fromethanol-ethyl acetate to afford 1.05 g of the title compound ascolorless crystals, m.p.163°-165° C.

Elemental Analysis for C₂₅ H₃₂ N₂ O.2HCl:

Calcd.: C, 66.81; H, 7.62; N, 6.23

Found : C, 66.65; H, 7.64; N, 6.17

WORKING EXAMPLE 6

Using the compound obtained in Reference Example 3, the procedure ofWorking Example 5 was followed to give compounds shown in Table 41.

                                      TABLE 41                                    __________________________________________________________________________     ##STR1076##                                                                   ##STR1077##                                                                         ##STR1078##                                                                     ##STR1079##                                                                                    ##STR1080##                                                                         ##STR1081##                                                                           ##STR1082##                           __________________________________________________________________________    1     H                                                                                ##STR1083##                                                                                    ##STR1084##                                                                         ##STR1085##                                                                           ##STR1086##                                                                       ##STR1087##                                                                      ##STR1088##                    2     H                                                                                ##STR1089##     183-186                                                                              ##STR1090##                                                                           ##STR1091##                                                                       ##STR1092##                                                                      ##STR1093##                    3     H                                                                                ##STR1094##                                                                                    ##STR1095##                                                                         ##STR1096##                                                                           ##STR1097##                                                                       ##STR1098##                                                                      ##STR1099##                    4     H                                                                                ##STR1100##                                                                                    ##STR1101##                                                                         ##STR1102##                                                                           ##STR1103##                                                                       ##STR1104##                                                                      ##STR1105##                    5     H                                                                                ##STR1106##     100-102                                                                             C.sub.31 H.sub.37 N.sub.3 O                                                            ##STR1107##                                                                       ##STR1108##                                                                      ##STR1109##                    __________________________________________________________________________

WORKING EXAMPLE 7 7-[N-ethyl-N-(phenylmethyl)amino]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-heptanone fumarate##STR1110## (1) A mixture of 1.7 g of ethylβ-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-β-oxopropionate,2.6 of 1,5-dibromopentane, 0.93 g of potassium carbonate and 50 ml ofacetone was heated for 16 hours under reflux. The reaction mixture wasleft standing for cooling, then the resulting solid matter was filteredoff. From the filtrate was distilled off the solvent. The residue waspurified by means of column chromatography (developing solvent;dichloromethane-ethyl acetate=10:1(V/V)) to afford 1.8 g of ethylβ-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-α-(5-bromopentyl)-β-oxopropionateas a viscous oily substance.

Elemental Analysis for C₂₂ H₃₀ BrNO₄ :

Calcd.: C, 58.41; H, 6.68; N, 3.10

Found : C, 58.26; H, 6.63; N, 3.04

(2) A solution of 0.5 g of the compound obtained in (1) and 0.3 g ofN-ethylbenzylamine in 10 ml of toluene was heated for 24 hours underreflux. The reaction mixture was left standing for cooling, then theresulting solid matter was filtered off. From the filtrate was distilledoff the solvent. To the residue was added 30 ml of conc. hydrochloricacid. The mixture was heated for 24 hours under reflux, then excessvolume of conc. hydrochloric acid was distilled off under reducedpressure. To the residue was added a 5% aqueous solution of sodiumhydroxide, which was subjected to extraction with dichloromethane. Theextract solution was dried over anhydrous sodium sulfate, from which thesolvent was distilled off. The residue was purified by means of columnchromatography (developing solvent; ethyl acetate-methanol=20:l(V/V)) togive 55 mg of a colorless oily product, which was processed with 16mg(one equivalent) of fumaric acid to afford 60 mg of the title compoundas an amorphous powder.

Elemental Analysis for C₂₆ H₃₆ N₂ O.C₄ H₄ O₄ :

Calcd.: C, 70.84; H, 7.93; N, 5.51

Found: C, 70.59; H, 8.04; N, 5.47

WORKING EXAMPLE 81-(3-Acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-(piperidin-1-yl)-1-ethanonehydrochloride ##STR1111##

In 10 ml of dichloromethane was dissolved 1.50 g of1-(3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-2-chloro-1-ethanoneobtained in Reference Example 2. To the solution was added 1.7 ml ofpiperidine, and the mixture was stirred for one hour at roomtemperature. The reaction mixture was poured into an aqueous solution ofpotassium carbonate, which was subjected to extraction withdichloromethane. The extract was dried over anhydrous sodium sulfate,from which was distilled off the solvent to leave an oily residue. Tothe residue was dissolved in 5 ml of methanol, to which was added 1.7 mlof 4N methanolic hydrochloric acid. Then the solvent was distilled offto leave 1.50 g of the title compound as colorless powder.

Elemental Analysis for C₁₉ H₂₆ N₂ O₂.HCl:

Calcd.: C, 65.04; H, 7.76; N, 7.98

Found : C, 64.92; H, 7.81; N, 7.87

WORKING EXAMPLE 91-[3-(Phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-2-(piperidin-1-yl)-1-ethanonedihydrochloride ##STR1112##

To 1.40 g of the compound obtained in Working Example 8 was added 20 mlof conc. hydrochloric acid. The mixture was stirred for 13 hours underreflux. The reaction mixture was cooled to 25° C., to which was added 50ml of pure water. The mixture was washed with 50 ml of dichloromethane.The aqueous layer was made basic with an aqueous solution of sodiumhdyroxide, which was subjected to extraction with 50 ml ofdichloromethane. The extract was dried over anhydrous sodium sulfate,from which was distilled off the solvent to leave 1.15 g of an oilyproduct.

To a suspension of 0.50 g of the above-mentioned oily product and 0.31 gof potassium carbonate in 10 ml of ethanol was added dropwise a solutionof 0.30 g of benzyl bromide in 5 ml of ethanol, and the mixture wasstirred for 16 hours at room temperature. The solvent was distilled off.To the residue were added 20 ml of dichloromethane and 20 ml of purewater. The organic layer was separated, dried over anhydrous sodiumsulfate, followed by distilling off the solvent. The residue wasdissolved in 10 ml of methanol, to which was added 1.1 ml of 4Nmethanolic hydrochloric acid. The solvent was then distilled off toleave a solid matter. Recrystallization from methanol-ethyl acetateafforded 0.2 g of the title compound as colorless crystals,m.p.236°-239° C. (decomp.).

Elemental Analysis for C₂₄ H₃₀ N₂ O.2HCl:

Calcd.: C, 66.20; H, 7.41; N, 6.43

Found: C, 66.11; H, 7.39; N, 6.38

WORKING EXAMPLE 10

Using the compounds obtained in Reference Example 1 or Reference Example5, the procedure of Working Example 1 was followed to give compoundsshown in Table 42, Table 43, Table 44 and Table 45.

                                      TABLE 42                                    __________________________________________________________________________     ##STR1113##                                                                   ##STR1114##                                                                         ##STR1115##                                                                        ##STR1116##                                                                     ##STR1117##                                                                     ##STR1118##                                                                     ##STR1119##                                                                                ##STR1120##                                                                         ##STR1121##                                                                          ##STR1122##                       __________________________________________________________________________    1     NAc  0 4 2                                                                                ##STR1123## 163-167                                                                              ##STR1124##                                                                          ##STR1125##                                                                       ##STR1126##                                                                      ##STR1127##                2     NCO.sub.2 Et                                                                       0 4 2                                                                                ##STR1128## 160-163                                                                              ##STR1129##                                                                          ##STR1130##                                                                       ##STR1131##                                                                      ##STR1132##                3     NCH.sub.2 Ph                                                                       2 2 2                                                                                ##STR1133## 198-202                                                                              ##STR1134##                                                                          ##STR1135##                                                                       ##STR1136##                                                                      ##STR1137##                4     NCH.sub.2 Ph                                                                       2 2 2                                                                                ##STR1138## 165-168                                                                              ##STR1139##                                                                          ##STR1140##                                                                       ##STR1141##                                                                      ##STR1142##                5     NCH.sub.2 Ph                                                                       2 2 2                                                                                ##STR1143## 176-179                                                                              ##STR1144##                                                                          ##STR1145##                                                                       ##STR1146##                                                                      ##STR1147##                6     NCH.sub.2 Ph                                                                       2 2 2                                                                                ##STR1148## 155-157                                                                              ##STR1149##                                                                          ##STR1150##                                                                       ##STR1151##                                                                      ##STR1152##                7     NCH.sub.2 Ph                                                                       2 2 2                                                                                ##STR1153## 181-184                                                                              ##STR1154##                                                                          ##STR1155##                                                                       ##STR1156##                                                                      ##STR1157##                8     NCH.sub.2 Ph                                                                       2 2 2                                                                                ##STR1158## 198-203                                                                              ##STR1159##                                                                          ##STR1160##                                                                       ##STR1161##                                                                      ##STR1162##                9     NCH.sub.2 Ph                                                                       2 2 2                                                                                ##STR1163##                                                                                ##STR1164##                                                                         ##STR1165##                                                                          ##STR1166##                                                                       ##STR1167##                                                                      ##STR1168##                __________________________________________________________________________     ##STR1169##                                                              

    TABLE 43      ##STR1170##      ##STR1171##      ##STR1172##      ##STR1173##      ##STR1174##      ##STR1175##      ##STR1176##      ##STR1177##      ##STR1178##                  10 NCH.sub.2      Ph 2 2 2     ##STR1179##      168-171 C.sub.30 H.sub.35 N.sub.3 O.3HCl.H.sub.2      O     ##STR1180##      ##STR1181##      ##STR1182##       11 NCH.sub.2      Ph 2 2 2     ##STR1183##      174-177 C.sub.32 H.sub.37 N.sub.3 O.sub.3.3HCl.3H.sub.2      O     ##STR1184##      ##STR1185##      ##STR1186##       12 NCH.sub.2      Ph 2 2 2     ##STR1187##      amorphous powder C.sub.29 H.sub.33 ClN.sub.2 O.sub.2.2HCl.2H.sub.2 O      ##STR1188##      ##STR1189##      ##STR1190##       13 NCH.sub.2      Ph 2 2 2     ##STR1191##      137-139 C.sub.44 H.sub.52 N.sub.4 O.sub.2.1/2H.sub.2      O     ##STR1192##      ##STR1193##      ##STR1194##       14 NCH.sub.2      Ph 2 2 2     ##STR1195##      243-248 (decomp.) C.sub.31 H.sub.35 ClN.sub.2      O.sub.2.2HCl     ##STR1196##      ##STR1197##      ##STR1198##       15 NCH.sub.2      Ph 2 2 1     ##STR1199##      amorphous powder C.sub.30 H.sub.35 N.sub.3 O.3HCl.5/2H.sub.2      O     ##STR1200##      ##STR1201##      ##STR1202##       16 NCH.sub.2      Ph 2 2 5     ##STR1203##      182-185 C.sub.34 H.sub.43 N.sub.3      O.3HCl     ##STR1204##      ##STR1205##      ##STR1206##      17 NAc 2 2 3     ##STR1207##      122-125 C.sub.27 H.sub.35 N.sub.3      O.sub.2     ##STR1208##      ##STR1209##      ##STR1210##

                                      TABLE 44                                    __________________________________________________________________________     ##STR1211##                                                                         ##STR1212##                                                                        ##STR1213##                                                                     ##STR1214##                                                                     ##STR1215##                                                                     ##STR1216##                                                                                  ##STR1217##                                                                         ##STR1218##                                                                           ##STR1219##                    __________________________________________________________________________    *18   NCHO 0 2 2                                                                                ##STR1220##   194-196                                                                              ##STR1221##                                                                           ##STR1222##                                                                       ##STR1223##                                                                      ##STR1224##              19   NCHO 1 3 2                                                                                ##STR1225##                                                                                  ##STR1226##                                                                         ##STR1227##                                                                           ##STR1228##                                                                       ##STR1229##                                                                      ##STR1230##             *20   NCHO 0 2 2                                                                                ##STR1231##    82-84                                                                              C.sub.23 H.sub.27 N.sub.3 O.sub.2                                                      ##STR1232##                                                                       ##STR1233##                                                                      ##STR1234##              21   NCH.sub.2 Ph                                                                       2 2 2                                                                                ##STR1235##   186-189                                                                              ##STR1236##                                                                           ##STR1237##                                                                       ##STR1238##                                                                      ##STR1239##              22   NCHO 2 2 2                                                                                ##STR1240##   106-108                                                                             C.sub.25 H.sub.31 N.sub.3 O.sub.2                                                      ##STR1241##                                                                       ##STR1242##                                                                      ##STR1243##              23   NAc  2 2 4                                                                                ##STR1244##   191-194                                                                              ##STR1245##                                                                           ##STR1246##                                                                       ##STR1247##                                                                      ##STR1248##              24   NCH.sub.2 Ph                                                                       2 2 2                                                                                ##STR1249##   168-172                                                                              ##STR1250##                                                                           ##STR1251##                                                                       ##STR1252##                                                                      ##STR1253##              25   NCH.sub.2 Ph                                                                       2 2 2                                                                                ##STR1254##   138-139                                                                              ##STR1255##                                                                           ##STR1256##                                                                       ##STR1257##                                                                      ##STR1258##             __________________________________________________________________________

                                      TABLE 45                                    __________________________________________________________________________     ##STR1259##                                                                         ##STR1260##                                                                         ##STR1261##                                                                     ##STR1262##                                                                     ##STR1263##                                                                     ##STR1264##                                                                               ##STR1265##                                                                         ##STR1266##                                                                           ##STR1267##                      __________________________________________________________________________     26   NCH.sub.2 Ph                                                                        2 2 2                                                                                ##STR1268##                                                                              140-142                                                                             C.sub.37 H.sub.41 N.sub.3 O                                                            ##STR1269##                                                                       ##STR1270##                                                                      ##STR1271##                27   NCO.sub.2 CH.sub.3                                                                  2 2 2                                                                                ##STR1272##                                                                               98-101                                                                             C.sub. 26 H.sub.33 N.sub.3 O.sub.3                                                     ##STR1273##                                                                       ##STR1274##                                                                      ##STR1275##               *28   NCHO  0 2 2                                                                                ##STR1276##                                                                               ##STR1277##                                                                         ##STR1278##                                                                           ##STR1279##                                                                       ##STR1280##                                                                      ##STR1281##                29   NCH.sub.2 Ph                                                                        2 2 2                                                                                ##STR1282##                                                                               ##STR1283##                                                                         ##STR1284##                                                                           ##STR1285##                                                                       ##STR1286##                                                                      ##STR1287##                30   NCHO  0 3 2                                                                                ##STR1288##                                                                               ##STR1289##                                                                         ##STR1290##                                                                           ##STR1291##                                                                       ##STR1292##                                                                      ##STR1293##               *31   NCHO  0 2 2                                                                                ##STR1294##                                                                              oil   C.sub.24 H.sub.29 N.sub.3 O.sub.2                                                      ##STR1295##                                                                       ##STR1296##                                                                      ##STR1297##                32   NCHO  0 3 2                                                                                ##STR1298##                                                                               ##STR1299##                                                                         ##STR1300##                                                                           ##STR1301##                                                                       ##STR1302##                                                                      ##STR1303##                33   NCHO  0 5 2                                                                                ##STR1304##                                                                               ##STR1305##                                                                         ##STR1306##                                                                           ##STR1307##                                                                       ##STR1308##                                                                      ##STR1309##                34   NAc   0 5 2                                                                                ##STR1310##                                                                               ##STR1311##                                                                         ##STR1312##                                                                           ##STR1313##                                                                       ##STR1314##                                                                      ##STR1315##               __________________________________________________________________________

WORKING EXAMPLE 113-[4-(Phenylmethyl)piperazin-1-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanonetrihydrochloride ##STR1316##

In 100 ml of 6N hydrochloric acid was dissolved 2.0 g of the compoundNo.2 in Working Example 10. The solution was heated for 16 hours underreflux. Hydrochloric acid was distilled off under reduced pressure. Theresidue was dissolved in water, which was neutralized with a 5% aqueoussolution of sodium hydroxide, followed by extraction withdichloromethane. The extract solution was dried over anhydrous sodiumsulfate, from which was distilled off the solvent. The residue waspurified by means of column chromatography (developing solvent; ethylacetate-methanol=40:1 (v/v) to give 1.2 g of the starting compound (freebase) and 0.3 g of the title compound (free base). The title compound(free base) (0.3 g) was treated with triequivalent hydrochloric acid toafford 0.35 g of the title compound (trihydrochloride) as colorlesspowder, m.p.145°-149° C.

Elemental Analysis for C₂₄ H₃₁ N₃ O.3HCl:

Calcd.: C, 59.20; H, 7.04; N, 8.63

Found : C, 59.04; H, 7.20; N, 8.53

WORKING EXAMPLE 121-(2,3,4,5-Tetrahydro-1H-3-benzazepin-7-Yl)-4-[4-(phenylmethyl)piperazin-1-yl)-1-butanonetrihydrochloride ##STR1317##

To 2.17 g of1-(3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4-(phenylmethyl)piperazin-1-yl]-1-butanone,i.e. Compound No. 17 in Working Example 10, was added 50 ml of conc.hydrochloric acid. The mixture was heated for 24 hours under reflux.Excess amount of conc. hydrochloric acid was distilled off under reducedpressure. To the residue was added 50 ml of water. The mixture waswashed with 50 ml of dichloromethane. The aqueous layer was made basicwith an aqueous solution of sodium hydroxide, which was subjected toextraction with dichloromethane. The extract solution was dried overanhydrous sodium sulfate. The solvent was distilled off to give 2.0 g ofan oily product.

The above-mentioned oily product was dissolved in methanol, to which wasadded 4.5 ml of 4N-methanolic hydrochloric acid. The solvent wasdistilled off to leave colorless crystals. The crystals were suspendedin 50 ml of ethyl acetate-ether (1:1), followed by collecting thecrystals by filtration to give 2.1 g of the title compound as colorlesscrystals, m.p.201°-204° C.

Elemental Analysis for C₂₅ H₃₃ N₃ O.3HCl.H₂ O:

Calcd.: C, 57.86; H, 7.38; N, 8.10

Found : C, 57.46; H, 7.36; N, 8.28

WORKING EXAMPLE 13

Using the compound obtained in Working Example 10, the procedure ofWorking Example 11 (procedure A) or the procedure of Working Example 12(procedure B) was followed to give compounds shown in Table 46.

                                      TABLE 46                                    __________________________________________________________________________     ##STR1318##                                                                   ##STR1319##                                                                          ##STR1320##                                                                        ##STR1321##                                                                         ##STR1322##                                                                     ##STR1323##                                                                     ##STR1324##                                                                     ##STR1325##                                                                                ##STR1326##                                                                         ##STR1327##                                                                            ##STR1328##              __________________________________________________________________________     1     A    NH    2 2 2                                                                                ##STR1329## 170-173                                                                              ##STR1330##                                                                            ##STR1331##                                                                       ##STR1332##                                                                      ##STR1333##       *2     A    NH    0 2 2                                                                                ##STR1334##                                                                                ##STR1335##                                                                         ##STR1336##                                                                            ##STR1337##                                                                       ##STR1338##                                                                      ##STR1339##        3     A    NH    1 3 2                                                                                ##STR1340##                                                                                ##STR1341##                                                                         ##STR1342##                                                                            ##STR1343##                                                                       ##STR1344##                                                                      ##STR1345##        4     B    NH    2 2 4                                                                                ##STR1346## 228-233                                                                              ##STR1347##                                                                            ##STR1348##                                                                       ##STR1349##                                                                      ##STR1350##        5     A    NCH.sub.2 Ph                                                                        2 2 2                                                                                ##STR1351## 187-190                                                                              ##STR1352##                                                                            ##STR1353##                                                                       ##STR1354##                                                                      ##STR1355##       *6     A    NH    0 2 2                                                                                ##STR1356##  97-99                                                                              C.sub.22 H.sub.27 N.sub.3                                                               ##STR1357##                                                                       ##STR1358##                                                                      ##STR1359##       *7     A    NH    0 2 2                                                                                ##STR1360##                                                                                ##STR1361##                                                                         ##STR1362##                                                                            ##STR1363##                                                                       ##STR1364##                                                                      ##STR1365##        8     A    NH    0 3 2                                                                                ##STR1366##                                                                                ##STR1367##                                                                         ##STR1368##                                                                            ##STR1369##                                                                       ##STR1370##                                                                      ##STR1371##       *9     A    NH    0 2 2                                                                                ##STR1372## 159-163                                                                              ##STR1373##                                                                            ##STR1374##                                                                       ##STR1375##                                                                      ##STR1376##       10     A    NH    0 3 2                                                                                ##STR1377##                                                                                ##STR1378##                                                                         ##STR1379##                                                                            ##STR1380##                                                                       ##STR1381##                                                                      ##STR1382##       11     A    NH    0 5 2                                                                                ##STR1383##                                                                                ##STR1384##                                                                         ##STR1385##                                                                            ##STR1386##                                                                       ##STR1387##                                                                      ##STR1388##       __________________________________________________________________________     ##STR1389##                                                              

WORKING EXAMPLE 14

By using the compound obtained in Working Example 13, the procedure ofWorking Example 1 was followed to give compounds shown in Tables 47-51.

                                      TABLE 47                                    __________________________________________________________________________     ##STR1390##                                                                   ##STR1391##                                                                         ##STR1392##                                                                             ##STR1393##                                                                     ##STR1394##                                                                     ##STR1395##                                                                     ##STR1396##                                                                                    ##STR1397##                                                                         ##STR1398##                                                                           ##STR1399##             __________________________________________________________________________    *1    NCH.sub.2 Ph                                                                            0 2 2                                                                                ##STR1400##     172-174                                                                              ##STR1401##                                                                           ##STR1402##                                                                       ##STR1403##                                                                      ##STR1404##       2    NCH.sub.2 Ph                                                                            1 3 2                                                                                ##STR1405##                                                                                    ##STR1406##                                                                         ##STR1407##                                                                           ##STR1408##                                                                       ##STR1409##                                                                      ##STR1410##       3    NCH.sub.2 Ph                                                                            2 2 4                                                                                ##STR1411##     234-238                                                                              ##STR1412##                                                                           ##STR1413##                                                                       ##STR1414##                                                                      ##STR1415##       4                                                                                   ##STR1416##                                                                            2 2 2                                                                                ##STR1417##                                                                                    ##STR1418##                                                                         ##STR1419##                                                                           ##STR1420##                                                                       ##STR1421##                                                                      ##STR1422##       5    NC.sub.2 H.sub.5                                                                        2 2 2                                                                                ##STR1423##                                                                                    ##STR1424##                                                                         ##STR1425##                                                                           ##STR1426##                                                                       ##STR1427##                                                                      ##STR1428##       6    NCH.sub.2 Ph                                                                            2 2 2                                                                                ##STR1429##     168-171                                                                              ##STR1430##                                                                           ##STR1431##                                                                       ##STR1432##                                                                      ##STR1433##       7    NCH.sub.2 Ph                                                                            2 2 2                                                                                ##STR1434##     176-180                                                                              ##STR1435##                                                                           ##STR1436##                                                                       ##STR1437##                                                                      ##STR1438##       8    NCH.sub.2 Ph                                                                            2 2 2                                                                                ##STR1439##     173-176                                                                              ##STR1440##                                                                           ##STR1441##                                                                       ##STR1442##                                                                      ##STR1443##      *9    NCH.sub.2 Ph                                                                            0 2 2                                                                                ##STR1444##                                                                                    ##STR1445##                                                                         ##STR1446##                                                                           ##STR1447##                                                                       ##STR1448##                                                                      ##STR1449##      __________________________________________________________________________     ##STR1450##                                                              

                                      TABLE 48                                    __________________________________________________________________________     ##STR1451##                                                                   ##STR1452##                                                                       ##STR1453##                                                                                ##STR1454##                                                                     ##STR1455##                                                                     ##STR1456##                                                                     ##STR1457##                                                                                    ##STR1458##                                                                        ##STR1459##                                                                           ##STR1460##             __________________________________________________________________________    10                                                                                 ##STR1461## 2 2 2                                                                                ##STR1462##     130-132                                                                            C.sub.31 H.sub.36 ClN.sub.3                                                   O                                                                                      ##STR1463##                                                                       ##STR1464##                                                                      ##STR1465##      11                                                                                 ##STR1466## 2 2 2                                                                                ##STR1467##                                                                                    ##STR1468##                                                                        ##STR1469##                                                                           ##STR1470##                                                                       ##STR1471##                                                                      ##STR1472##      12                                                                                 ##STR1473## 2 2 2                                                                                ##STR1474##     170-172                                                                             ##STR1475##                                                                           ##STR1476##                                                                       ##STR1477##                                                                      ##STR1478##      13                                                                                 ##STR1479## 2 2 2                                                                                ##STR1480##     161-163                                                                             ##STR1481##                                                                           ##STR1482##                                                                       ##STR1483##                                                                      ##STR1484##      14                                                                                 ##STR1485## 2 2 2                                                                                ##STR1486##                                                                                    ##STR1487##                                                                        ##STR1488##                                                                           ##STR1489##                                                                       ##STR1490##                                                                      ##STR1491##      15  NCH.sub.2 Ph 2 2 2                                                                                ##STR1492##                                                                                    ##STR1493##                                                                        ##STR1494##                                                                           ##STR1495##                                                                       ##STR1496##                                                                      ##STR1497##      16  NCH.sub.2 Ph 2 2 2                                                                                ##STR1498##     172-175                                                                             ##STR1499##                                                                           ##STR1500##                                                                       ##STR1501##                                                                      ##STR1502##      17  NCH.sub.2 Ph 2 2 2                                                                                ##STR1503##     110-113                                                                            C.sub.29 H.sub.35 N.sub.3                                                     O.sub.2                                                                                ##STR1504##                                                                       ##STR1505##                                                                      ##STR1506##      18  NCH.sub.2 Ph 2 2 2                                                                                ##STR1507##                                                                                    ##STR1508##                                                                        ##STR1509##                                                                           ##STR1510##                                                                       ##STR1511##                                                                      ##STR1512##      __________________________________________________________________________

                                      TABLE 49                                    __________________________________________________________________________     ##STR1513##                                                                   ##STR1514##                                                                          ##STR1515##                                                                                  ##STR1516##                                                                     ##STR1517##                                                                     ##STR1518##                                                                     ##STR1519##                                                                              ##STR1520##                                                                         ##STR1521##                                                                           ##STR1522##             __________________________________________________________________________    19                                                                                    ##STR1523##   2 2 2                                                                                ##STR1524##                                                                              ##STR1525##                                                                         ##STR1526##                                                                           ##STR1527##                                                                       ##STR1528##                                                                      ##STR1529##      20                                                                                    ##STR1530##   2 2 2                                                                                ##STR1531##                                                                             165-168                                                                              ##STR1532##                                                                           ##STR1533##                                                                       ##STR1534##                                                                      ##STR1535##      21                                                                                    ##STR1536##   2 2 2                                                                                ##STR1537##                                                                              ##STR1538##                                                                         ##STR1539##                                                                           ##STR1540##                                                                       ##STR1541##                                                                      ##STR1542##      22                                                                                    ##STR1543##   2 2 2                                                                                ##STR1544##                                                                              ##STR1545##                                                                         ##STR1546##                                                                           ##STR1547##                                                                       ##STR1548##                                                                      ##STR1549##      23                                                                                    ##STR1550##   2 2 2                                                                                ##STR1551##                                                                              ##STR1552##                                                                         ##STR1553##                                                                           ##STR1554##                                                                       ##STR1555##                                                                      ##STR1556##      24                                                                                    ##STR1557##   2 2 2                                                                                ##STR1558##                                                                             178-180                                                                              ##STR1559##                                                                           ##STR1560##                                                                       ##STR1561##                                                                      ##STR1562##      25                                                                                    ##STR1563##   2 2 2                                                                                ##STR1564##                                                                              ##STR1565##                                                                         ##STR1566##                                                                           ##STR1567##                                                                       ##STR1568##                                                                      ##STR1569##      26                                                                                    ##STR1570##   2 2 2                                                                                ##STR1571##                                                                             170-172                                                                              ##STR1572##                                                                           ##STR1573##                                                                       ##STR1574##                                                                      ##STR1575##      27                                                                                    ##STR1576##   2 2 2                                                                                ##STR1577##                                                                             173-176                                                                              ##STR1578##                                                                           ##STR1579##                                                                       ##STR1580##                                                                      ##STR1581##      __________________________________________________________________________

                                      TABLE 50                                    __________________________________________________________________________     ##STR1582##                                                                   ##STR1583##                                                                         ##STR1584##                                                                                   ##STR1585##                                                                     ##STR1586##                                                                     ##STR1587##                                                                     ##STR1588##                                                                              ##STR1589##                                                                         ##STR1590##                                                                           ##STR1591##             __________________________________________________________________________    28                                                                                   ##STR1592##    2 2 2                                                                                ##STR1593##                                                                             177-180                                                                              ##STR1594##                                                                           ##STR1595##                                                                       ##STR1596##                                                                      ##STR1597##      29                                                                                   ##STR1598##    2 2 2                                                                                ##STR1599##                                                                             181-184                                                                              ##STR1600##                                                                           ##STR1601##                                                                       ##STR1602##                                                                      ##STR1603##      30                                                                                   ##STR1604##    2 2 2                                                                                ##STR1605##                                                                              ##STR1606##                                                                         ##STR1607##                                                                           ##STR1608##                                                                       ##STR1609##                                                                      ##STR1610##      31    NCH.sub.2 CH.sub.2 Ph                                                                         2 2 2                                                                                ##STR1611##                                                                              ##STR1612##                                                                         ##STR1613##                                                                           ##STR1614##                                                                       ##STR1615##                                                                      ##STR1616##      32                                                                                   ##STR1617##    2 2 2                                                                                ##STR1618##                                                                             193-196                                                                              ##STR1619##                                                                           ##STR1620##                                                                       ##STR1621##                                                                      ##STR1622##      33    NCH.sub.2 CH(CH.sub.3).sub.2                                                                  2 2 2                                                                                ##STR1623##                                                                             167-170                                                                              ##STR1624##                                                                           ##STR1625##                                                                       ##STR1626##                                                                      ##STR1627##      34                                                                                   ##STR1628##    2 2 2                                                                                ##STR1629##                                                                              ##STR1630##                                                                         ##STR1631##                                                                           ##STR1632##                                                                       ##STR1633##                                                                      ##STR1634##      35                                                                                   ##STR1635##    2 2 2                                                                                ##STR1636##                                                                              ##STR1637##                                                                         ##STR1638##                                                                           ##STR1639##                                                                       ##STR1640##                                                                      ##STR1641##      36                                                                                   ##STR1642##    2 2 2                                                                                ##STR1643##                                                                              ##STR1644##                                                                         ##STR1645##                                                                           ##STR1646##                                                                       ##STR1647##                                                                      ##STR1648##      __________________________________________________________________________

                                      TABLE 51                                    __________________________________________________________________________     ##STR1649##                                                                   ##STR1650##                                                                       ##STR1651##                                                                              ##STR1652##                                                                     ##STR1653##                                                                     ##STR1654##                                                                     ##STR1655##                                                                                     ##STR1656##                                                                         ##STR1657##                                                                           ##STR1658##             __________________________________________________________________________     37 NCH.sub.2 CH.sub.2 CH.sub.3                                                              2 2 2                                                                                ##STR1659##      177-179                                                                              ##STR1660##                                                                           ##STR1661##                                                                       ##STR1662##                                                                      ##STR1663##       38                                                                                ##STR1664##                                                                             2 2 2                                                                                ##STR1665##      168-170                                                                              ##STR1666##                                                                           ##STR1667##                                                                       ##STR1668##                                                                      ##STR1669##       39 NCH.sub.2 CH.sub.2 OH                                                                    2 2 2                                                                                ##STR1670##      166-169                                                                              ##STR1671##                                                                           ##STR1672##                                                                       ##STR1673##                                                                      ##STR1674##       40                                                                                ##STR1675##                                                                             2 2 2                                                                                ##STR1676##      168-170                                                                              ##STR1677##                                                                           ##STR1678##                                                                       ##STR1679##                                                                      ##STR1680##       41                                                                                ##STR1681##                                                                             2 2 2                                                                                ##STR1682##      168-171                                                                              ##STR1683##                                                                           ##STR1684##                                                                       ##STR1685##                                                                      ##STR1686##      *42 NCH.sub.2 Ph                                                                             0 2 2                                                                                ##STR1687##      185-187                                                                              ##STR1688##                                                                           ##STR1689##                                                                       ##STR1690##                                                                      ##STR1691##       43 NCH.sub.2 Ph                                                                             2 2 2                                                                                ##STR1692##                                                                                     ##STR1693##                                                                         ##STR1694##                                                                           ##STR1695##                                                                       ##STR1696##                                                                      ##STR1697##      __________________________________________________________________________     ##STR1698##                                                              

WORKING EXAMPLE 153-Diphenylamino-1-[3-(phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-propanonehydrochloride ##STR1699##

To a solution of 0.98 g of the Compound No. 5 of Reference Example 5 in30 ml of 1,2-dichloroethane was added 0.63 ml of triethylamine. Themixture was stirred for one hour at room temperature, to which was added0.56 g of diphenylamine, followed by heating for 72 hours under reflux.The reaction mixture was cooled to room temperature, which was thenpoured into 50 ml of pure water. To the mixture was added a 1N aqueoussolution of sodium hydroxide. The aqueous layer was adjusted to pH notlower than 12, followed by extraction with dichloromethane. The extractsolution was dried over anhydrous sodium sulfate, then the solvent wasdistilled off to leave an oily product. The oily product was purified bymeans of a silica gel column chromatography (developing solvent:dichloromethane-ethyl acetate=4:1 (v/v)) to afford 0.30 g of the freebase of the title compound. The free base was added to 4N methanolichydrochloric acid, then the solvent was distilled off. The residue wastriturated from diethyl ether-hexane to afford 0.25 g of the titlecompound as amorphous powder.

Elemental Analysis for C₃₂ H₃₂ N₂ O.HCl.H₂ O:

Calcd.: C, 74.62; H, 6.85; N, 5.44

Found : C, 74.29; H, 6.91; N, 5.40

WORKING EXAMPLE 161-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(phenylmethyl)piperazin-1-yl]-1-propanonedihydrochloride ##STR1700##

To a solution of 0.7 g of the Compound No.6 of Working Example 13 in 40ml of dichloromethane was added dropwise 0.2 g of acetic arthydride. Themixture was stirred for 2 hours at room temperature. To the reactionmixture was added a saturated aqueous solution of sodiumhydrogencarbonate, followed by extraction with dichloromethane. Theextract solution was dried over anhdyrous sodium sulfate, then thesolvent was distilled off. The residue was crystallized from diethylether to give 0.54 g of the free base of the title compound as paleyellow crystals, m.p.107°-109° C.

To 0.35 g of the above-mentioned free base was added 4N methanolichydrochloric acid (2 equivalents), followed by distilling off thesolvent to afford 0.35 g of the title compound as crystalline powder,m.p.216°-218° C.

Elemental Analysis for C₂₄ H₂₉ N₃ O₂.2HCl.2H₂ O:

Calcd.: C, 57.60; H, 7.05; N, 8.40

Found : C, 57.47; H, 6.86; N, 8.26

WORKING EXAMPLE 17

Using the compound of Working Example 13, the procedure of WorkingExample 16 was followed to afford the compounds shown in Table 52.

                                      TABLE 52                                    __________________________________________________________________________     ##STR1701##                                                                   ##STR1702##                                                                         ##STR1703##                                                                             ##STR1704##                                                                     ##STR1705##                                                                     ##STR1706##                                                                     ##STR1707##                                                                             ##STR1708##                                                                         ##STR1709##                                                                           ##STR1710##                    __________________________________________________________________________     1    NAc       1 3 2                                                                                ##STR1711##                                                                            196-200                                                                              ##STR1712##                                                                           ##STR1713##                                                                       ##STR1714##                                                                      ##STR1715##             *2    NAc       2 0 2                                                                                ##STR1716##                                                                             ##STR1717##                                                                         ##STR1718##                                                                           ##STR1719##                                                                       ##STR1720##                                                                      ##STR1721##              3    NCOPh     2 2 2                                                                                ##STR1722##                                                                            148-151                                                                              ##STR1723##                                                                           ##STR1724##                                                                       ##STR1725##                                                                      ##STR1726##              4                                                                                   ##STR1727##                                                                            2 2 2                                                                                ##STR1728##                                                                             ##STR1729##                                                                         ##STR1730##                                                                           ##STR1731##                                                                       ##STR1732##                                                                      ##STR1733##              5    NCONHCH.sub.3                                                                           2 2 2                                                                                ##STR1734##                                                                            162-164                                                                              ##STR1735##                                                                           ##STR1736##                                                                       ##STR1737##                                                                      ##STR1738##             *6    NAc       3 0 2                                                                                ##STR1739##                                                                             ##STR1740##                                                                         ##STR1741##                                                                           ##STR1742##                                                                       ##STR1743##                                                                      ##STR1744##             __________________________________________________________________________     ##STR1745##                                                              

WORKING EXAMPLE 181-(3-Methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-3-[4-(phenylmethyl)piperazin-1-yl]-1-propanonetrihydrochloride ##STR1746##

In 30 ml of ethanol was suspended 0.50 g of the compound obtained inReference Example 6, to which were added 0.55 g of potassium carbonateand 0.42 ml of 1benzyl piperazine at room temperature. The mixture wasstirred for 3 hours, to which were added 50 ml of dichloromethane and 50ml of pure water. The organic layer was separated and washed with 30 mlof pure water, which was then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to leave 0.2 g of anoily residue. The oily residue was purified by means of an aluminachromatography (developing solvent: dichloromethane-ethyl acetate=4: 1(v/v)) to give 0.17 g an oily residue. To the oily residue was added 3equivalents of mathanolic hydrochloric acid, then methanol was distilledoff to afford 0.2 g of the title compound as amorphous powder.

Elemental Analysis for C₂₅ H₃₃ N₃ O.2HCl.3H₂ O:

Calcd.: C, 55.92; H, 7.51; N, 7.83

Found : C, 56.01; H, 7.78; N, 7.83

WORKING EXAMPLE 19 1- [3- (Phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-2-phenyl-4-(piperidin-1-yl)-1-butanone dihydrochloride ##STR1747##

In 20 ml of dichloromethane was dissolved 0.92 g (2 mmol.) of thecompound No.1 obtained in Reference Example 9. To the solution was added0.99 ml (10 mmol.) of piperidine, and the mixture was stirred for oneday at room temperature. The reaction mixture was washed with 20 ml of1N aqueous solution of sodium hydroxide and 20 ml of pure water,followed by drying over sodium sulfate. The solvent was distilled offunder reduced pressure. The residue was purified by means of a silicagel column chromatography [developing solvent: ethyl acetate-methanol(4:1)] to afford 0.53 g of the title compound in the free form as anoily substance.

To the oily substance was added 4N-methanolic hydrochloric acid (2equivalents), then the solvent was distilled off under reduced pressureto give 0.58 g of the title compound as a hydroscopic amorphous powder.

Elemental Analysis for C₃₂ H₃₈ N₂ O.2HCl.H₂ O:

Calcd.: C, 68.93; H, 7.59; N, 5.02

Found : C, 69.01; H, 7.55; N, 5.05

WORKING EXAMPLE 20

By substantially the same procedure as in Working Example 19, using thecompounds obtained in Reference Example 8 or Reference Example 9,compounds shown in Table 53 were obtained.

                                      TABLE 53                                    __________________________________________________________________________     ##STR1748##                                                                   ##STR1749##                                                                         ##STR1750##                                                                        ##STR1751##                                                                     ##STR1752##                                                                     ##STR1753##                                                                     ##STR1754##                                                                     ##STR1755##                                                                             ##STR1756##                                                                         ##STR1757##                                                                          ##STR1758##                        __________________________________________________________________________    1     NCH.sub.2 Ph                                                                       2 2 Ph                                                                              3 N(CH.sub.3).sub.2                                                                       amorphous                                                                           C.sub. 29 H.sub.34 N.sub.2 O                                                         65.04                                                                             7.53                                                                             5.23                                                      powder                                                                              .2HCl.2H.sub.2 O                                                                     (65.17                                                                            7.51                                                                             5.20)                        2     NCHO 2 2 Ph                                                                              3                                                                                ##STR1759##                                                                             ##STR1760##                                                                         ##STR1761##                                                                          ##STR1762##                                                                       ##STR1763##                                                                      ##STR1764##                 __________________________________________________________________________

FORMULATION EXAMPLE 1

(1)3-[4-(Phenylmethyl)piperazin-1-yl]-1-[3-(phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-propanonetrihydrochloride (Compound No.1 in [Table 17], Working Example 6) 1 g

(2) Lactose 197 g

(3) Corn starch 50 g

(4) Magnesium stearate 2 g

(1), (2) and 20 g of corn starch were blended and the mixture wasgranulated with a paste prepared from 15 g of corn starch and 25 ml ofwater. To this granular product were added 15 g of corn starch and (4),and the resulting composition was compression-molded to provide 2000tablets each measuring 3 mm in diameter and containing 0.5 mg of (1).

FORMULATION EXAMPLE 2

(1)3-[4-(phenylmethyl)piperazin-1-yl]-1-[3-(phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-propanonetrihydrochloride (Compound No.1 in [Table 17], Working Example 6) 2 g

(2) Lactose 197 g

(3) Corn starch 50 g

(4) Magnesium stearate 2 g

(1), (2) and 20 g of corn starch were blended and the mixture wasgranulated with a paste prepared from 15 g of corn starch and 25 ml ofwater. To this granular product were added 15 g of corn starch and (4),and the resulting composition was compression-molded to provide 2000tablets each measuring 3 mm in diameter and containing 1.0 mg of (1).

EXPERIMENTAL EXAMPLE 1

The cholinesterase inhibitory activity of the compound of this inventionwas assayed with (acetyl-[³ H])-acetylcholine. More specifically, usingthe S₁ fraction of a homogenate of male Wistar rat cerebral cortex asthe cholinesterase source, (acetyl[³ H])-acetylcholine as the substrateand the compound of this invention as the test sample were added. Themixture was incubated for 30 minutes, then the reaction was terminated,to which was added a toluene-based scintillant, then the mixture wasshaken. The reaction product [³ H]-acetic acid was transferred to thetoluene layer, which was subjected to determination of cholinesteraseactivity by counting with a liquid scintillation counter.

The cholinesterase inhibitory activity of the test compound wasexpressed in 50% inhibitory concentration (IC₅₀). The cholinesteraseactivity of physostigmine was also determined by the same procedure. Theresults are shown in Table 54.

                  TABLE 54                                                        ______________________________________                                        Compound        Acetylcholinesterase inhibitory                               (Working Example No.)                                                                         activity IC.sub.50 (μM)                                    ______________________________________                                        3-4             0.119                                                         6-1             0.049                                                         6-5             0.0526                                                        10-18           0.0152                                                        10-19           0.171                                                         10-20           0.0152                                                        10-22           0.0928                                                        10-26           0.0526                                                        10-27           0.169                                                         10-30           0.0599                                                        10-32           0.118                                                         13-1            0.0493                                                        13-3            0.0789                                                        13-8            0.163                                                         14-2            0.0538                                                        14-4            0.147                                                         14-5            0.0188                                                        14-6            0.113                                                         14-10           0.167                                                         14-14           0.0636                                                        14-19           0.0339                                                        14-20           0.0478                                                        14-21           0.0226                                                        14-22           0.0215                                                        14-23           0.0661                                                        14-25           0.0696                                                        14-27           0.133                                                         14-29           0.0257                                                        14-31           0.033                                                         14-33           0.0341                                                        14-36           0.0168                                                        14-40           0.0602                                                        16              0.0251                                                        17-3            0.0825                                                        18              0.0338                                                        Physostigmine   0.220                                                         ______________________________________                                    

The results shown in Table 54 indicate that the compound of the presentinvention has superior cholinesterase inhibitory activity tophysostigmine.

EXPERIMENTAL EXAMPLE 2

Effects of the compound of this invention on monoamine uptake wereinvestigated using [³ H]-norepinephirine(NE) and [³ H]-serotonin (5-HT).Rats were sacrificed by decapitation. The cerebral cortex andhippocampus were removed and homogenized in 10-15 volumes (W/V) of anice-cold medium containing 0.32M sucrose. Crude synaptosomalpreparations (P2) were isolated after differential centrifugation at1000× g for 10 min and 20,000× g for 30 min at 4° C. Synaptosomalmembranes were suspended in Krebs-Ringer bicarbonate (KRB) solution (116mM NaC₁, 4.8 mM KCl, 1.3 mM CaCl₂, 1.2 mMMgSO₄, 1.2 mM NaH₂ PO₄, 25 mMNaHCO₃, 0.1 mM EDTA-2Na, 11.1 mM glucose, 0.11 mM ascorbic acid, 0.01 mMpargyline). Synaptosomal membrane suspension (900 μl ) was preincubatedwith the test compound dissolved in DMSO solution at 37° C. for 5 min.The reaction was initiated by addition of 100 μl of [³ H]-NE(11 nM infinal concentration) or [³ H]-5-HT (10 nM in final concentration). Fiveminutes later, the reaction was stopped by the addition of 4 ml ofice-cold KRB and the reaction mixture was filtered through Whatman GF/B.Filters were washed twice with 4 ml of KRB and the radioactivity boundwas counted with liquid scintillant. Imipramine and desipramine wereused as positive control All compounds were tested at 10⁻⁸, 10⁻⁷, 10⁻⁶and 10⁻⁵ _(M). The results are shown in Table 55 .

                  TABLE 55                                                        ______________________________________                                                            Monoamine reup-                                                               take inhibitory                                           Compound            activity IC.sub.50 (μM)                                (Working Example No.)                                                                             NE     5-HT                                               ______________________________________                                        14-1                0.147  0.416                                              14-6                0.725  0.0345                                             14-7                0.822  0.0421                                             14-23               0.912  0.0583                                             14-29               0.429  0.0544                                             14-31               0.441  0.0305                                             14-33               0.74   0.0559                                             14-36               0.70   0.0133                                             14-40               0.359  0.0413                                             Desipramine         0.15   0.45                                               Imipramine          1.12   0.063                                              ______________________________________                                    

The results shown in Table 55 indicate that the compound of the presentinvention has superior inhibitory activity of monoamine uptake toreference compounds such as desipramine or imipramine.

EFFECTS OF INVENTION

The compound of the present invention has excellent cholinesteraseinhibitory activity and monoamine reuptake inhibitory activity and isuseful as therapeutic/prophylactic medicament of senile dementia.

What is claimed is:
 1. A compound of the formula: ##STR1765## wherein R¹is H, an optionally substituted hydrocarbon group or an optionallysubstituted acyl group; ring A is an optionally further substitutedbenzene ring; n is a whole number of 1 to 10; R², is H or an optionallysubstituted hydrocarbon group; R³ and R⁴ form an optionally substitutedheterocyclic group, taken together with the adjacent nitrogen atom; R²'s may be different from one another in the repetition of n; k is awhole number of 0 to 3; and m is a whole number of 1 to 8; provided thatwhen k=0 and m=2, n is a whole number of not less than 2, and providedthat k+m=2 to 5; or a pharmaceutically acceptable salt thereof.
 2. Acompound as claimed in claim 1, wherein R¹ is (1) a hydrogen atom, (2) astraight-chain or branched C₁₋₁₁ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynylgroup which may be substituted by 1 to 5 substituents selected from thegroup consisting of a halogen, nitro, cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄alkylthio, amino, mono- or di-C₁₋₄ alkyl-substituted amino, 5 to7-membered cyclic amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkylsulfonylamino, C₁₋₄ alkoxy-carbonyl, carboxyl, C₁₋₆ alkyl-carbonyl,carbamoyl, mono- or di-C₁₋₄ alkyl-substituted carbamoyl, C₁₋₆alkylsulfonyl, C₁₋₄ alkylenedioxy and heterocyclic group, (3) a C₃₋₇monocyclic cycloalkyl group which may be substituted by 1 to 5substituents selected from the group consisting of a halogen, nitro,cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄ alkylthio, amino, mono- or di-C₁₋₄alkyl-substituted amino, 5 to 7-membered cyclic amino, C₁₋₄alkyl-carbonylamino, C₁₋₄ alkylsulfonylamino, C₁₋₄ alkoxy-carbonyl,carboxyl, C₁₋₆ alkyl-carbonyl, carbamoyl, mono- or di-C₁₋₄alkyl-substituted carbamoyl, C₁₋₆ alkylsulfonyl, C₁₋₄ alkylenedioxy andheterocyclic group, (4) a C₈₋₁₄ bridge ring saturated hydrocarbon groupwhich may be substituted by 1 to 5 substituents selected from the groupconsisting of a halogen, nitro, cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄alkylthio, amino, mono- or di-C₁₋₄ alkyl-substituted amino, 5 to7-membered cyclic amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkylsulfonylamino, C₁₋₄ alkoxy-carbonyl, carboxyl, C₁₋₆ alkyl-carbonyl,carbamoyl, mono- or di-C₁₋₄ alkyl-substituted carbamoyl, C₁₋₆alkylsulfonyl, C₁₋₄ alkylenedioxy and heterocyclic group, (5) a phenylor naphthyl group which may be substituted by 1 to 5 substituentsselected from the group consisting of a C₁₋₄ alkyl, halogen, nitro,cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄ alkylthio, amino, mono- or di-C₁₋₄alkyl-substituted amino, 5 to 7-membered cyclic amino, C₁₋₄alkyl-carbonylamino, C₇₋₁₈ aralkyloxy, aminocarbonyloxy, mono- ordi-C₁₋₄ alkyl-substituted aminocarbonyloxy, C₁₋₄ alkylsulfonylamino,C₁₋₄ alkoxy-carbonyl, carboxyl, C₁₋₆ alkyl-carbonyl, C₃₋₇cycloalkyl-carbonyl, carbamoyl, mono- or di-C₁₋₄ alkyl-substitutedcarbamoyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkylsulfonyl and a phenyl,naphthyl, mono- or di-phenyl-C₁₋₃ alkyl, phenoxy, benzoyl,phenoxycarbonyl, benzylcarbonyl, phenyl-C₁₋₄ alkyl-carbamoyl,phenylcarbamoyl, phenyl-C₁₋₄ alkyl-carbonylamino, benzoylamino,phenyl-C₁₋₄ alkylsulfonyl, phenylsulfonyl, phenyl-C₁₋₄ alkylsulfinyl,phenyl-C₁₋₄ alkylsulfonylamino or phenylsulfonylamino group which may besubstituted by 1 to 4 substituents selected from the group consisting ofa C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, hydroxy, benzyloxy, amino, mono- ordi-C₁₋₄ alkyl-substituted amino, nitro, C₁₋₆ alkyl-carbonyl and benzoyl,(6) a C₇₋₁₈ aralkyl, C₆₋₁₄ aryl-C₂₋₁₂ alkenyl, C₆₋₁₄ aryl-C₂₋₁₂ alkynylor C₃₋₇ cycloalkyl-C₁₋₆ alkyl group which may be substituted by 1 to 5substituents selected from the group consisting of a C₁₋₄ alkyl,halogen, nitro, cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄ alkylthio, amino,mono- or di-C₁₋₄ alkyl-substituted amino, 5 to 7-membered cyclic amino,C₁₋₄ alkyl-carbonylamino, C₇₋₁₈ aralkyloxy, aminocarbonyloxy, mono- ordi-C₁₋₄ alkyl-substituted aminocarbonyloxy, C₁₋₄ alkylsulfonylamino,C₁₋₄ alkoxy-carbonyl, carboxyl, C₁₋₆ alkyl-carbonyl, C₃₋₇cycloalkyl-carbonyl, carbamoyl, mono- or di-C₁₋₄ alkyl-substitutedcarbamoyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkylsulfonyl and a phenyl,naphthyl, mono- or di-phenyl-C₁₋₃ alkyl, phenoxy, benzoyl,phenoxycarbonyl, benzylcarbonyl, phenyl-C₁₋₄ alkyl-carbamoyl,phenylcarbamoyl, phenyl-C₁₋₄ alkyl-carbonylamino, benzoylamino,phenyl-C₁₋₄ alkylsulfonyl, phenylsulfonyl, phenyl-C₁₋₄ alkylsulfinyl,phenyl-C₁₋₄ alkylsulfonylamino or phenylsulfonylamino group which may besubstituted by 1 to 4 substituents selected from the group consisting ofa C.sub. 1-4 alkyl, C₁₋₄ alkoxy, halogen, hydroxy, benzyloxy, amino,mono- or di-C₁₋₄ alkyl-substituted amino, nitro, C₁₋₆ alkyl-carbonyl andbenzoyl, (7) a C₁₋₈ alkyl-carbonyl or C₆₋₁₄ aryl-carbonyl group whichmay be substituted by 1 to 3 substituents selected from the groupconsisting of a halogen, amino, mono- or di-C₁₋₆ alkyl substituted aminoand C₁₋₄ alkoxy, (8) a C₁₋₇ alkylsulfonyl or C₆₋₁₄ arylsulfonyl groupwhich may be substituted by 1 to 3 substituents selected from the groupconsisting of a halogen, amino, mono- or di-C₁₋₆ alkyl substituted aminoand C₁₋₄ alkoxy, (9) a C₁₋₇ alkylphosphonyl or C₆₋₁₄ arylphosphonylgroup which may be substituted by 1 to 3 substituents selected from thegroup consisting of a halogen, amino, mono- or di-C₁₋₆ alkyl substitutedamino and C₁₋₄ alkoxy, (10) a C₁₋₈ alkoxy-carbonyl or C₇₋₁₈aralkyloxy-carbonyl group which may be substituted by 1 to 3substituents selected from the group consisting of a halogen, amino,mono- or di-C₁₋₆ alkyl substituted amino and C₁₋₄ alkoxy, (11)heterocyclic-carbonyl group which may be substituted by 1 to 3substituents selected from the group consisting of a halogen, amino,mono- or di-C₁₋₆ alkyl substituted amino and C₁₋₄ alkoxy, (12) carbamoylgroup which may be substituted by 1 to 3 substituents selected from thegroup consisting of a halogen, amino, mono- or di-C₁₋₆ alkyl substitutedamino and C₁₋₄ alkoxy, (13) mono- or di-C₁₋₄ alkyl-carbamoyl group whichmay be substituted by 1 to 3 substituents selected from the groupconsisting of a halogen, amino, mono- or di-C₁₋₆ alkyl substituted aminoand C₁₋₄ alkoxy, or (14) formyl; R² is (1') a hydrogen atom, (2') astraight-chain or branched C₁₋₁₁ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynylgroup which may be substituted by 1 to 5 substituents selected from thegroup consisting of a halogen, nitro, cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄alkylthio, amino, mono- or di-C₁₋₄ alkyl-substituted amino, 5 to7-membered cyclic amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkylsulfonylamino, C₁₋₄ alkoxy-carbonyl, carboxyl, C₁₋ 6alkyl-carbonyl, carbamoyl, mono- or di-C₁₋₄ alkyl-substituted carbamoyl,C₁₋₆ alkylsulfonyl, C₁₋₄ alkylenedioxy and heterocyclic group, (3') aC₃₋₇ monocyclic cycloalkyl group which may be substituted by 1 to 5substituents selected from the group consisting of a halogen, nitro,cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄ alkylthio, amino, mono- or di-C₁₋₄alkyl-substituted amino, 5 to 7-membered cyclic amino, C₁₋ 4alkyl-carbonylamino, C₁₋₄ alkylsulfonylamino, C₁₋₄ alkoxy-carbonyl,carboxyl, C₁₋₆ alkyl-carbonyl, carbamoyl, mono- or di-C₁₋₄alkyl-substituted carbamoyl, C₁₋₆ alkylsulfonyl, C₁₋₄ alkylenedioxy andheterocyclic group, (4') a C₈₋₁₄ bridge ring saturated hydrocarbon groupwhich may be substituted by 1 to 5 substituents selected from the groupconsisting of a halogen, nitro, cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄alkylthio, amino, mono- or di-C₁₋₄ alkyl-substituted amino, 5 to7-membered cyclic amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkylsulfonylamino, C₁₋₄ alkoxy-carbonyl, carboxyl, C₁₋₆ alkyl-carbonyl,carbamoyl, mono- or di-C₁₋₄ alkyl-substituted carbamoyl, C₁₋₆alkylsulfonyl, C₁₋₄ alkylenedioxy and heterocyclic group, (5') a phenylor naphthyl group which may be substituted by 1 to 5 substituentsselected from the group consisting of a C₁₋₄ alkyl, halogen, nitro,cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄ alkylthio, amino, mono- or di-C₁₋₄alkyl-substituted amino, 5 to 7-membered cyclic amino, C₁₋₄alkyl-carbonylamino, C₇₋₁₈ aralkyloxy, aminocarbonyloxy, mono- ordi-C₁₋₄ alkyl-substituted aminocarbonyloxy, C₁₋₄ alkylsulfonylamino,C₁₋₄ alkoxy-carbonyl, carboxyl, C₁₋₆ alkyl-carbonyl, C₃₋₇cycloalkyl-carbonyl, carbamoyl, mono- or di-C₁₋₄ alkyl-substitutedcarbamoyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkylsulfonyl and a phenyl,naphthyl, mono- or di-phenyl-C₁₋₃ alkyl, phenoxy, benzoyl,phenoxycarbonyl, benzylcarbonyl, phenyl-C₁₋₄ alkyl-carbamoyl,phenylcarbamoyl, phenyl-C₁₋₄ alkyl-carbonylamino, benzoylamino,phenyl-C₁₋₄ alkylsulfonyl, phenylsulfonyl, phenyl-C₁₋₄ alkylsulfinyl,phenyl-C₁₋₄ alkylsulfonylamino or phenylsulfonylamino group which may besubstituted by 1 to 4 substituents selected from the group consisting ofa C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, hydroxy, benzyloxy, amino, mono- ordi-C₁₋₄ alkyl-substituted amino, nitro, C₁₋₆ alkyl-carbonyl and benzoyl,(6') a C₇₋₁₈ aralkyl, C₆₋₁₄ aryl-C₂₋₁₂ alkenyl, C₆₋₁₄ aryl-C₂₋₁₂ alkynylor C₃₋₇ cycloalkyl-C₁₋₆ alkyl group which may be substituted by 1 to 5substituents selected from the group consisting of a C₁₋₄ alkyl,halogen, nitro, cyano, hydroxy, C₁₋₄ alkoxy, alkylthio, amino, mono- ordi-C₁₋₄ alkyl-substituted amino, 5 to 7-membered cyclic amino, C₁₋₄alkyl-carbonylamino, C₇₋₁₈ aralkyloxy, aminocarbonyloxy, mono- ordi-C₁₋₄ alkyl-substituted aminocarbonyloxy, C₁₋₄ alkylsulfonylamino,C₁₋₄ alkoxy-carbonyl, carboxyl, C₁₋₆ alkyl-carbonyl, C₃₋₇cycloalkyl-carbonyl, carbamoyl, mono- or di-C₁₋₄ alkyl-substitutedcarbamoyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkylsulfonyl and a phenyl,naphthyl, mono- or di-phenyl-C₁₋₃ alkyl, phenoxy, benzoyl,phenoxycarbonyl, benzylcarbonyl, phenyl-C₁₋₄ alkyl-carbamoyl,phenylcarbamoyl, phenyl-C₁₋₄ alkyl-carbonylamino, benzoylamino,phenyl-C₁₋₄ alkylsulfonyl, phenylsulfonyl, phenyl-C₁₋₄ alkylsulfinyl,phenyl-C₁₋₄ alkylsulfonylamino or phenylsulfonylamino group which may besubstituted by 1 to 4 substituents selected from the group consisting ofa C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, hydroxy, benzyloxy, amino, mono- ordi-C₁₋₄ alkyl-substituted amino, nitro, C₁₋₆ alkyl-carbonyl and benzoyl,R³ and R⁴ taken together with the adjacent nitrogen atom, form a 3- to13-membered heterocyclic group having, other than carbon atoms and onenitrogen atom, 1 to 3 nitrogen, oxygen and/or sulfur atoms as heteroatoms, which may be substituted by 1 to 5 substituents selected from thegroup consisting of (1") a straight-chain or branched C₁₋₁₁ alkyl, C₂₋₄alkenyl or C₂₋₄ alkynyl group which may be substituted by 1 to 5substituents selected from the group consisting of a halogen, nitro,cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄ alkylthio, amino, mono- or di-C₁₋₄alkyl-substituted amino, 5 to 7-membered cyclic amino, C₁₋₄alkyl-carbonylamino, C₁₋₄ alkylsulfonylamino, C₁₋₄ alkoxy-carbonyl,carboxyl, C₁₋₆ alkyl-carbonyl, carbamoyl, mono- or di-C₁₋₄alkyl-substituted carbamoyl, C₁₋₆ alkylsulfonyl, C₁₋₄ alkylenedioxy andheterocyclic group, (2") a C₃₋₇ monocyclic cycloalkyl group which may besubstituted by 1 to 5 substituents selected from the group consisting ofa halogen, nitro, cyano, hydroxy, C₁₋ 4 alkoxy, C₁₋₄ alkylthio, amino,mono- or di-C₁₋₄ alkyl-substituted amino, 5 to 7-membered cyclic amino,C₁₋₄ alkyl-carbonylamino, C₁₋₄ alkylsulfonylamino, C₁₋₄ alkoxy-carbonyl,carboxyl, C₁₋₆ alkyl-carbonyl, carbamoyl, mono- or di-C₁₋₄alkyl-substituted carbamoyl, C₁₋₆ alkylsulfonyl, C₁₋₄ alkylenedioxy andheterocyclic group, (3") a C₈₋₁₄ bridge ring saturated hydrocarbon groupwhich may be substituted by 1 to 5 substituents selected from the groupconsisting of a halogen, nitro, cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄alkylthio, amino, mono- or di-C₁₋₄ alkyl-substituted amino, 5 to7-membered cyclic amino, C₁₋₄ alkyl-carbonylamino, C₁₋₄alkylsulfonylamino, C₁₋₄ alkoxy-carbonyl, carboxyl, C₁₋₆ alkyl-carbonyl,carbamoyl, mono- or di-C₁₋₄ alkyl-substituted carbamoyl, C₁₋₆alkylsulfonyl, C₁₋₄ alkylenedioxy and heterocyclic group, (4") a phenylor naphthyl group which may be substituted by 1 to 5 substituentsselected from the group consisting of a C₁₋₄ alkyl, halogen, nitro,cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄ alkylthio, amino, mono- or di-C₁₋₄alkyl-substituted amino, 5 to 7-membered cyclic amino, C₁₋₄alkyl-carbonylamino, C₇₋₁₈ aralkyloxy, aminocarbonyloxy, mono- ordi-C₁₋₄ alkyl-substituted aminocarbonyloxy, C₁₋₄ alkylsulfonylamino,C₁₋₄ alkoxy-carbonyl, carboxyl, alkyl-carbonyl, C₃₋₇cycloalkyl-carbonyl, carbamoyl, mono- or di-C₁₋₄ alkyl-substitutedcarbamoyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkylsulfonyl, C₁₋₄alkylenedioxy and a phenyl, naphthyl, mono- or di-phenyl-C₁₋₃ alkyl,phenoxy, benzoyl, phenoxycarbonyl, benzylcarbonyl, phenyl-C₁₋₄alkyl-carbamoyl, phenylcarbamoyl, phenyl-C₁₋₄ alkyl-carbonylamino,benzoylamino, phenyl-C₁₋₄ alkylsulfonyl, phenylsulfonyl, phenyl-C₁₋₄alkylsulfinyl, phenyl-C₁₋₄ alkylsulfonylamino or phenylsulfonylaminogroup which may be substituted by 1 to 4 substituents selected from thegroup consisting of a C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, hydroxy,benzyloxy, amino, mono- or di-C₁₋₄ alkyl-substituted amino, nitro, C₂₋₆alkyl-carbonyl and benzoyl, (5") a C₇₋₁₈ aralkyl, C₆ ₁₄ aryl-C₂₋₁₂alkenyl, C₆₋₁₄ aryl-C₂₋₁₂ alkynyl or C₃₋₇ cycloalkyl-C₁₋₆ alkyl groupwhich may be substituted by 1 to 5 substituents selected from the groupconsisting of a C₁₋ 4 alkyl, halogen, nitro, cyano, hydroxy, C₁₋₄alkoxy, C₁₋₄ alkylthio, amino, mono- or di-C₁₋₄ alkyl-substituted amino,5 to 7-membered cyclic amino, C₁₋₄ alkyl-carbonylamino, C₇₋₁₈aralkyloxy, aminocarbonyloxy, mono- or di-C₁₋₄ alkyl-substitutedaminocarbonyloxy, C₁₋₄ alkylsulfonylamino, C₁₋₄ alkoxy-carbonyl,carboxyl, C₁₋₆ alkyl-carbonyl, C₃₋₇ cycloalkyl-carbonyl, carbamoyl,mono- or di-C₁₋₄ alkyl-substituted carbamoyl, C.sub. 1-6 alkylsulfonyl,C₃₋₇ cycloalkylsulfonyl, C₁₋₄ alkylenedioxy and a phenyl, naphthyl,mono- or di-phenyl-C₁₋₃ alkyl, phenoxy, benzoyl, phenoxycarbonyl,benzylcarbonyl, phenyl-C₁₋₄ alkyl-carbamoyl, phenylcarbamoyl,phenyl-C₁₋₄ alkyl-carbonylamino, benzoylamino, phenyl-C₁₋₄alkylsulfonyl, phenylsulfonyl, phenyl-C₁₋₄ alkylsulfinyl, phenyl-C₁₋₄alkylsulfonylamino or phenylsulfonylamino group which may be substitutedby 1 to 4 substituents selected from the group consisting of a C₁₋₄alkyl, C₁₋₄ alkoxy, halogen, hydroxy, benzyloxy, amino, mono- or di-C₁₋₄alkyl-substituted amino, nitro, C₁₋₆ alkyl-carbonyl and benzoyl, (6")halogen atom, (7") nitro group, (8") cyano group, (9") hydroxyl group,(10") C₁₋₄ alkoxy group, (11") C₁₋₄ alkylthio group, (12") amino group,(13") mono or di C₁₋₄ alkylamino group, (14") C₁₋₄ alkyl-carbonylaminogroup, (15") C₁₋₄ alkyl-sulfonylamino group, (16") C₁₋₄ alkoxy-carbonylgroup, (17") carboxyl group, (18") formyl group, (19") C₁₋₆alkyl-carbonyl group, (20") C₁₋₄ alkyl-carbonyloxy group, (21")ω-oxo-ω-(tetrahydrobenzazepinyl) C₁₋₆ alkyl group, (22") benzoyl groupwhich may be substituted by 1 to 3 substituents selected from the groupconsisting of C₁₋₄ alkyl, halogen, C₁₋₄ alkoxy, mono- or di-C₁₋₄alkylamino, 5- to 7-membered cyclic amino group, nitro and hydroxy,(23") carbamoyl group, (24") mono or di C₁₋₄ alkyl-carbamoyl group,(25") C₁₋₆ alkylsulfonyl group, (26") oxo group and (27") heterocyclicgroup selected from pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl,isoquinolinyl, naphthylidinyl, benzothiazolyl, benzoxazolyl, furanyl andthiophenyl; ring A is a benzene ring which may be further substituted by1 to 3 substituents selected from the group consisting of a C₁₋₄ alkyl,halogen, nitro, cyano, hydroxy, C₁₋₄ alkoxy, C₁₋₄ alkylthio, amino,mono- or di-C₁₋₄ alkyl-substituted amino, 5 to 7-membered cyclic amino,C₁₋₄ alkyl-carbonylamino, C₇₋₁₈ aralkyloxy, aminocarbonyloxy, mono- ordi-C₁₋₄ alkyl-substituted aminocarbonyloxy, C₁₋₄ alkylsulfonylamino,C₁₋₄ alkoxy-carbonyl, carboxyl, C₁₋₆ alkyl-carbonyl, C₃₋₇cycloalkyl-carbonyl, carbamoyl, mono- or di-C₁₋₄ alkyl-substitutedcarbamoyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkylsulfonyl and a phenyl,naphthyl, mono- or di-phenyl-C₁₋₃ alkyl, phenoxy, benzoyl,phenoxycarbonyl, benzylcarbonyl, phenyl-C₁₋₄ alkyl-carbamoyl,phenylcarbamoyl, phenyl-C₁₋₄ alkyl-carbonylamino, benzoylamino,phenyl-C₁₋₄ alkylsulfonyl, phenylsulfonyl, phenyl-C₁₋₄ alkylsulfinyl,phenyl-C₁₋₄ alkylsulfonylamino or phenylsulfonylamino which may besubstituted by 1 to 4 substituents selected from the group consisting ofa C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, hydroxy, benzyloxy, amino, mono- ordi-C₁₋₄ alkyl-substituted amino, nitro, C₁₋₆ alkyl-carbonyl and benzoyl.3. A compound as claimed in claim 1, wherein R¹ is(i) hydrogen atom,(ii) a C₁₋₄ alkyl group which may be substituted with a hydroxy group,(iii) a C₂₋₄ alkynyl group, (iv) a phenyl-C₁₋₃ alkyl group which may besubstituted with one to three substituents selected from the groupconsisting of a halogen, nitro, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxyand phenylmethoxy group, (v) formyl group, (vi) a C₁₋₄ alkyl-carbonylgroup, (vii) benzoyl group, (viii) a C₁₋₄ alkoxy-carbonyl group, (ix)pyridylcarbonyl group, or (x) a mono- or di-C₁₋₄ alkylcarbamoyl group.4. A compound as claimed in claim 1, wherein R¹ is (i) H, (ii) astraight-chain or branched C₁₋₄ alkyl group, (iii) a phenyl-C₁₋₃ alkylgroup which may be substituted by 1 to 3 substituents selected from thegroup consisting of C₁₋₄ alkyl, halogen, nitro, cyano, hydroxy, C₁₋₄alkoxy and C₇₋₁₈ aralkyloxy, (iv) a naphthyl-C₁₋₃ alkyl group, (v) aC₁₋₃ alkyl-carbonyl, (vi) a phenyloxycarbonyl or (vii) a C₁₋₄alkoxy-carbonyl.
 5. A compound as claimed in claim 1, wherein R¹ is (i)H, (ii) a straight-chain or branched C₁₋₄ alkyl group, (iii) a C₁₋₄alkyl-carbonyl group or (iv) a phenyl-C₁₋₃ alkyl group which may besubstituted by a C₁₋₄ alkoxy.
 6. A compound as claimed in claim 1,wherein k is a whole number of 0 to 2 and m is a whole number of 2 to 5.7. A compound as claimed in claim 1, wherein the moiety in the formula[I ] of ##STR1766## and R¹ is (i) H, (ii) a straight-chain or branchedC₁₋₄ alkyl group, (iii) a C₁₋₃ alkyl-carbonyl group or (iv) aphenyl-C₁₋₃ alkyl group which may be substituted by a C₁₋₄ alkoxy.
 8. Acompound as claimed in claim 1, wherein the ring A is a benzene ring. 9.A compound as claimed in claim 1, wherein n is a whole number of 1 to 6.10. A compound as claimed in claim 1, wherein R² is hydrogen atom orphenyl group.
 11. A compound as claimed in claim 1, wherein R² is H. 12.A compound as claimed in claim 1, wherein R³ and R⁴, taken together withthe adjacent nitrogen atom, form(i') a piperidinyl group which may besubstituted with a phenyl-C₁₋₃ alkyl group, a hydroxy group or oxo,(ii') 4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decan-8-yl, (iii')1,2,3,4-tetrahydroisoquinolin-2-yl, (iv') pyrrolidinyl, (v')morpholinyl, (vi') a homopiperazinyl group which may be substituted witha phenyl-C₁₋₃ alkyl group, or (vii') a piperazinyl group which may besubstituted with (1) a phenyl-C₁₋₃ alkyl group which may be substitutedwith a halogen atom, a C₁₋₄ alkoxy group or a C₁₋₄ alkylenedioxy group,(2) pyridyl group, (3) a benzoyl group which may be substituted with ahalogen atom, (4) a C₁₋₄ alkyl group which may be substituted withhydroxy group,3-oxo-3[3-(phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]propyl,pyridyl, furyl or 2-methyl-thiazol-4-yl group, (5) formyl group, (6) aC₁₋₆ alkyl-carbonyl group, (7) a phenyl group which may be substitutedwith a halogen atom, (8) hydroxyl group or (9) a diphenyl-C₁₋₃ alkylgroup.
 13. A compound as claimed in claim 1, wherein R³ and R⁴ takentogether with the adjacent nitrogen atom, form a pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl or 1,2,3,4-tetrahydroquinolinylgroup which may be substituted by 1 or 2 substituents selected from thegroup consisting of (1) formyl, (2) C₁₋₄ alkylcarbonyl, (3) hydroxy, (4)oxo, (5) pyridyl, (6) benzoyl which may be substituted by 1 to 3 halogenatoms, (7) straight-chain or branched C₁₋₇ alkyl which may besubstituted by 1 to 3 substituents selected from the group consisting ofhydroxy, pyridyl, furyl, thiazol-4-yl and 2-methyl-thiazol-4-yl, (8)phenyl which may be substituted by 1 to 3 substituents selected from thegroup consisting of halogen, hydroxy and C₁₋₄ alkylenedioxy, (9) C₇₋₁₈aralkyl which may be substituted by 1 to 3 substituents selected fromthe group consisting of halogen, hydroxy and C₁₋₄ alkylenedioxy and (10)ω-oxo-ω-(tetrahydrobenzazepinyl) C₁₋₆ alkyl.
 14. A compound as claimedin claim 1, wherein R³ and R⁴ taken together with the adjacent nitrogenatom, form a 4-(phenylmethyl)-piperazin-1-yl or4-[(2-methylthiazol-4-yl)methyl]-piperazin-1-yl.
 15. A compound asclaimed in claim 1, wherein n is a whole number of 2 to
 5. 16. Acompound as claimed in claim 1, which is a compound of the formula:##STR1767## wherein R^(1a) is (i) a C₁₋₄ alkyl group or(ii) aphenyl-C₁₋₃ alkyl group which may be substituted with a C₁₋₄ alkoxygroup,or a pharmaceutically acceptable salt thereof.
 17. A compound asclaimed in claim 1, which is1-[3-[(4-methoxyphenyl)methyl]-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-3-[4-(phenylmethyl)piperazin-1-yl]-1-propanoneor a pharmaceutically acceptable salt thereof.
 18. A compound as claimedin claim 1, which is1-[3-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-3-[4-(phenylmethyl)piperazin-1-yl]-1-propanoneor a pharmaceutically acceptable salt thereof.
 19. A compound as claimedin claim 1, which is1-[3-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-3-[4-(phenylmethyl)piperazin-1-yl]-1-propanoneor a pharmaceutically acceptable salt thereof.
 20. A compound as claimedin claim 1, which is1-[3-(phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-3-[4-(phenylmethyl)piperazin-1-yl]-1-propanoneor a pharmaceutically acceptable salt thereof.
 21. A compound as claimedin claim 1, which is1-[1-(phenylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-[4-(phenylmethyl)piperazin-1-yl]-1-propanoneor a pharmaceutically acceptable salt thereof.
 22. A compound as claimedin claim 1, which is1-[2-(phenylmethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]-3-[4-(phenylmethyl)piperazin-1-yl]-1-propanoneor a pharmaceutically acceptable salt thereof.
 23. A compound as claimedin claim 1, which is3-[4-[(2-methylthiazol-4-yl)methyl]piperazin-1-yl]-1-[3-(phenylmethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-propanoneor a pharmaceutically acceptable salt thereof.
 24. A compound of theformula: ##STR1768## wherein R¹ is H, an optionally substitutedhydrocarbon group or an optionally substituted acyl group; ring A is anoptionally substituted benzene ring; n is a whole number of 1 to 10; R²,R³ and R⁴ are independently H or an optionally substituted hydrocarbongroup, provided one of R³ and R⁴ is H or a straight-chain or branchedC₁₋₄ alkyl group and the other is a straight-chain or branched C₁₋₄alkyl group, a phenyl-C₁₋₃ alkyl group or a naphthyl-C₁₋₃ alkyl group;the R² 's may be different from one another in the repetition of n; k isa whole number of 0 to 3; and m is a whole number of 1 to 8; providedthat when k=0 and m=2, n is a whole number of not less than 2; andprovided that k+m=2 to 5; or a pharmaceutically acceptable salt thereof.25. A pharmaceutical composition for a disease caused byacetylcholinesterase activity which contains an effective cholinesteraseinhibiting amount of a compound of the formula as claimed in claim 1 ora pharmaceutically acceptable salt thereof and a pharmacologicallyacceptable carrier.
 26. A pharmaceutical composition as claimed in claim25, in which the disease is senile dementia and/or Alzheimer's disease.27. A method of treating a disease caused by acetylcholinesteraseactivity which comprises administering a therapeutically effectiveamount of a compound of the formula: ##STR1769## wherein X¹ is R¹ --N(R¹ is H, an optionally substituted hydrocarbon group or an optionallysubstituted acyl group); ring A is an optionally further substitutedbenzene ring; n is a whole number of 1 to 10; R², R³ and R⁴ areindependently H or an optionally substituted hydrocarbon group; R³ andR⁴ may form an optionally substituted heterocyclic group, taken togetherwith the adjacent nitrogen atom; R² 's may be different from one anotherin the repetition of n; k is a whole number of 0 to 3; and m is a wholenumber of 1 to 8, and provided that k+m=2 to 5; or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablecarrier to a mammal suffering from such disease.